216 results on '"Groudine M"'
Search Results
2. Rearrangement and Amplification of c-abl Sequences in the Human Chronic Myelogenous Leukemia Cell line K-562
- Author
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Collins, S. J. and Groudine, M. T.
- Published
- 1983
3. Molecular basis for chromatin binding and regulation of MLL5
- Author
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Rincon-Arano, H., Kutateladze, T. G., Zhao, W., Tong, Q., Strahl, B. D., Deng, L.-W., Parkhurst, S. M., Groudine, M., Ali, M., and Rothbart, S. B.
- Abstract
The human mixed-lineage leukemia 5 (MLL5) protein mediates hematopoietic cell homeostasis, cell cycle, and survival; however, the molecular basis underlying MLL5 activities remains unknown. Here, we show that MLL5 is recruited to gene-rich euchromatic regions via the interaction of its plant homeodomain finger with the histone mark H3K4me3. The 1.48-Å resolution crystal structure of MLL5 plant homeodomain in complex with the H3K4me3 peptide reveals a noncanonical binding mechanism, whereby K4me3 is recognized through a single aromatic residue and an aspartate. The binding induces a unique His–Asp swapping rearrangement mediated by a C-terminal α-helix. Phosphorylation of H3T3 and H3T6 abrogates the association with H3K4me3 in vitro and in vivo, releasing MLL5 from chromatin in mitosis. This regulatory switch is conserved in the Drosophila ortholog of MLL5, UpSET, and suggests the developmental control for targeting of H3K4me3. Together, our findings provide first insights into the molecular basis for the recruitment, exclusion, and regulation of MLL5 at chromatin.
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- 2013
- Full Text
- View/download PDF
4. Fast neutron teletherapy for advanced carcinomas of the oral cavity and soft palate.
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Laramore, Gueorge E., Griffin, Thomas W., Tong, Daphne, Groudine, Mark T., Blasko, John C., Kurtz, John, Russell, Anthony H., Parker, Robert G., Laramore, G E, Griffin, T W, Tong, D, Groudine, M T, Blasko, J C, Kurtz, J, Russell, A H, and Parker, R G
- Published
- 1980
- Full Text
- View/download PDF
5. Electron Beam Therapy of Mycosis Fungoides.
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Blasko, J., Becker, L., Griffin, T. W., Tong, D. Y. K., and Groudine, M.
- Published
- 1979
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- View/download PDF
6. Fast Neutron Teletherapy for Advanced Carcinoma of Hypopharynx and Supraglottic Larynx.
- Author
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Laramore, G. E., Johnson, J., Griffin, T. W., Tong, D., Groudine, M. T., Kurtz, J. M., Russell, A. H., and Parker, R. G.
- Published
- 1980
- Full Text
- View/download PDF
7. Deregulation of cell cycle control in hematologic malignancies.
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Clurman, Bruce E., Roberts, James M., Groudine, Mark, Clurman, B E, Roberts, J M, and Groudine, M
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- 1996
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8. Sequences in the human c-myc P2 promoter affect the elongation and premature termination of transcripts initiated from the upstream P1 promoter
- Author
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Groudine, M [Univ. of Washington School of Medicine, Seattle, WA (United States)]
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- 1992
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9. Genetic complexity of transformation
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Groudine, M. and Weintraub, H.
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- 1977
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10. An integrated encyclopedia of DNA elements in the human genome
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Robert Altshuler, Laura Elnitski, Michael Anaya, Alec Victorsen, Deborah Winter, Javier Herrero, Katherine Varley, Andrea Sboner, Oscar Junhong Luo, Marco Mariotti, Cristina Sisu, Mike Kay, Timothy Dreszer, Jane Loveland, Alexandra Bignell, Ewan Birney, Tim @timjph Hubbard, Kuljeet Sandhu, Eric Haugen, Chris Gunter, Alexej Abyzov, Lucas Ward, Georgi Marinov, Michael Pazin, Thomas Gingeras, Alexander Dobin, Kimberly Foss, Xianjun Dong, Benoit Miotto, Piotr Mieczkowski, Cedric Notredame, Andrew Berry, Shawn Gillespie, Axel Visel, Shawn Levy, Richard Sandstrom, Jose M Gonzalez, Melissa Fullwood, Timo Lassmann, Michael Tress, Julien Lagarde, Kevin Yip, Leslie Adams, Sylvain Foissac, Bronwen Aken, Piero Carninci, Suganthi Balasubramanian, Andrea Tanzer, Sarah Djebali, Michael Hoffman, Gloria Despacio-Reyes, Peter Park, Felix Kokocinski, Katherine Fisher-Aylor, Juan M Vaquerizas, Peggy Farnham, Patrick Collins, Amonida Zadissa, Pedro Ferreira, Philippe Batut, Michael Snyder, Electra Tapanari, Adam Frankish, Paul Flicek, AMARTYA SANYAL, Tyler Alioto, Giovanni Bussotti, Laurence Meyer, Jingyi Jessica Li, Matthew Blow, Tristan FRUM, Roger Alexander, Rory Johnson, Charles Steward, Meizhen Zheng, Margus Lukk, Ross Hardison, Claire Davidson, Gary Saunders, Alan Boyle, Luiz Penalva, Rajinder Kaul, Lazaro Centanin, Florencia Pauli Behn, Thomas Derrien, Nathan Sheffield, Toby Hunt, Eric Nguyen, Jeff Vierstra, Konrad Karczewski, Kimberly Bell, Yanbao Yu, Hagen U Tilgner, James Taylor, Balázs Bánfai, Catherine Snow, Benjamin Vernot, Stephan Kirchmaier, Michael Sammeth, Steven Wilder, Angelika Merkel, Joanna Mieczkowska, Guoliang Li, Wei Lin, Jennifer Harrow, Thomas Oliver Auer, Daniel Barrell, Eddie Park, Alvis Brazma, Hazuki Takahashi, Nathan Johnson, Daniel Sobral, Terry Furey, Alexandre Reymond, Jonathan Mudge, Anshul Kundaje, Jose Rodriguez, Akshay Bhinge, James Gilbert, Jakub Karczewski, Venkat Malladi, Troy Whitfield, Orion Buske, Ian Dunham, Jennifer Moran, Joachim Wittbrodt, Charles B. Epstein, Laurens Wilming, Jason Gertz, Joshua Akey, Joel Rozowsky, Laboratoire de Génétique Cellulaire (LGC), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), National Human Genome Research Institute (NHGRI), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Antonarakis, Stylianos, Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Altshuler, Robert Charles, Ernst, Jason, Kellis, Manolis, Kheradpour, Pouya, Ward, Lucas D., Eaton, Matthew Lucas, Hendrix, David A., Jungreis, Irwin, Lin, Michael F., Washietl, Stefan, Lists of participants and their affiliations appear at the end of the paper and in the 'Collaboration/Projet' field., The Consortium is funded by grants from the NHGRI as follows: production grants: U54HG004570 (B. E. Bernstein), U01HG004695 (E. Birney), U54HG004563 (G. E. Crawford), U54HG004557 (T. R. Gingeras), U54HG004555 (T. J. Hubbard), U41HG004568 (W. J. Kent), U54HG004576 (R. M. Myers), U54HG004558 (M. Snyder), U54HG004592 (J. A. Stamatoyannopoulos). Pilot grants: R01HG003143 (J. Dekker), RC2HG005591 and R01HG003700 (M. C. Giddings), R01HG004456-03 (Y. Ruan), U01HG004571 (S. A. Tenenbaum), U01HG004561 (Z. Weng), RC2HG005679 (K. P. White). This project was supported in part by American Recovery and Reinvestment Act (ARRA) funds from the NHGRI through grants U54HG004570, U54HG004563, U41HG004568, U54HG004592, R01HG003143, RC2HG005591, R01HG003541,U01HG004561,RC2HG005679andR01HG003988(L. Pennacchio). In addition, work from NHGRI Groups was supported by the Intramural Research Program of the NHGRI (L. Elnitski, ZIAHG200323, E. H. Margulies, ZIAHG200341). Research in the Pennachio laboratory was performed at Lawrence Berkeley National Laboratory and at the United States Department of Energy Joint Genome Institute, Department of Energy Contract DE-AC02-05CH11231, University of California., Dunham I, Kundaje A, Aldred SF, Collins PJ, Davis CA, Doyle F, Epstein CB, Frietze S, Harrow J, Kaul R, Khatun J, Lajoie BR, Landt SG, Lee BK, Pauli F, Rosenbloom KR, Sabo P, Safi A, Sanyal A, Shoresh N, Simon JM, Song L, Trinklein ND, Altshuler RC, Birney E, Brown JB, Cheng C, Djebali S, Dong X, Dunham I, Ernst J, Furey TS, Gerstein M, Giardine B, Greven M, Hardison RC, Harris RS, Herrero J, Hoffman MM, Iyer S, Kellis M, Khatun J, Kheradpour P, Kundaje A, Lassmann T, Li Q, Lin X, Marinov GK, Merkel A, Mortazavi A, Parker SC, Reddy TE, Rozowsky J, Schlesinger F, Thurman RE, Wang J, Ward LD, Whitfield TW, Wilder SP, Wu W, Xi HS, Yip KY, Zhuang J, Pazin MJ, Lowdon RF, Dillon LA, Adams LB, Kelly CJ, Zhang J, Wexler JR, Green ED, Good PJ, Feingold EA, Bernstein BE, Birney E, Crawford GE, Dekker J, Elnitski L, Farnham PJ, Gerstein M, Giddings MC, Gingeras TR, Green ED, Guigó R, Hardison RC, Hubbard TJ, Kellis M, Kent W, Lieb JD, Margulies EH, Myers RM, Snyder M, Stamatoyannopoulos JA, Tenenbaum SA, Weng Z, White KP, Wold B, Khatun J, Yu Y, Wrobel J, Risk BA, Gunawardena HP, Kuiper HC, Maier CW, Xie L, Chen X, Giddings MC, Bernstein BE, Epstein CB, Shoresh N, Ernst J, Kheradpour P, Mikkelsen TS, Gillespie S, Goren A, Ram O, Zhang X, Wang L, Issner R, Coyne MJ, Durham T, Ku M, Truong T, Ward LD, Altshuler RC, Eaton ML, Kellis M, Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Röder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Batut P, Bell I, Bell K, Chakrabortty S, Chen X, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Gunawardena HP, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Li G, Luo OJ, Park E, Preall JB, Presaud K, Ribeca P, Risk BA, Robyr D, Ruan X, Sammeth M, Sandhu KS, Schaeffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Wrobel J, Yu Y, Hayashizaki Y, Harrow J, Gerstein M, Hubbard TJ, Reymond A, Antonarakis SE, Hannon GJ, Giddings MC, Ruan Y, Wold B, Carninci P, Guigó R, Gingeras TR, Rosenbloom KR, Sloan CA, Learned K, Malladi VS, Wong MC, Barber GP, Cline MS, Dreszer TR, Heitner SG, Karolchik D, Kent W, Kirkup VM, Meyer LR, Long JC, Maddren M, Raney BJ, Furey TS, Song L, Grasfeder LL, Giresi PG, Lee BK, Battenhouse A, Sheffield NC, Simon JM, Showers KA, Safi A, London D, Bhinge AA, Shestak C, Schaner MR, Kim SK, Zhang ZZ, Mieczkowski PA, Mieczkowska JO, Liu Z, McDaniell RM, Ni Y, Rashid NU, Kim MJ, Adar S, Zhang Z, Wang T, Winter D, Keefe D, Birney E, Iyer VR, Lieb JD, Crawford GE, Li G, Sandhu KS, Zheng M, Wang P, Luo OJ, Shahab A, Fullwood MJ, Ruan X, Ruan Y, Myers RM, Pauli F, Williams BA, Gertz J, Marinov GK, Reddy TE, Vielmetter J, Partridge E, Trout D, Varley KE, Gasper C, Bansal A, Pepke S, Jain P, Amrhein H, Bowling KM, Anaya M, Cross MK, King B, Muratet MA, Antoshechkin I, Newberry KM, McCue K, Nesmith AS, Fisher-Aylor KI, Pusey B, DeSalvo G, Parker SL, Balasubramanian S, Davis NS, Meadows SK, Eggleston T, Gunter C, Newberry J, Levy SE, Absher DM, Mortazavi A, Wong WH, Wold B, Blow MJ, Visel A, Pennachio LA, Elnitski L, Margulies EH, Parker SC, Petrykowska HM, Abyzov A, Aken B, Barrell D, Barson G, Berry A, Bignell A, Boychenko V, Bussotti G, Chrast J, Davidson C, Derrien T, Despacio-Reyes G, Diekhans M, Ezkurdia I, Frankish A, Gilbert J, Gonzalez JM, Griffiths E, Harte R, Hendrix DA, Howald C, Hunt T, Jungreis I, Kay M, Khurana E, Kokocinski F, Leng J, Lin MF, Loveland J, Lu Z, Manthravadi D, Mariotti M, Mudge J, Mukherjee G, Notredame C, Pei B, Rodriguez JM, Saunders G, Sboner A, Searle S, Sisu C, Snow C, Steward C, Tanzer A, Tapanari E, Tress ML, van Baren MJ, Walters N, Washietl S, Wilming L, Zadissa A, Zhang Z, Brent M, Haussler D, Kellis M, Valencia A, Gerstein M, Reymond A, Guigó R, Harrow J, Hubbard TJ, Landt SG, Frietze S, Abyzov A, Addleman N, Alexander RP, Auerbach RK, Balasubramanian S, Bettinger K, Bhardwaj N, Boyle AP, Cao AR, Cayting P, Charos A, Cheng Y, Cheng C, Eastman C, Euskirchen G, Fleming JD, Grubert F, Habegger L, Hariharan M, Harmanci A, Iyengar S, Jin VX, Karczewski KJ, Kasowski M, Lacroute P, Lam H, Lamarre-Vincent N, Leng J, Lian J, Lindahl-Allen M, Min R, Miotto B, Monahan H, Moqtaderi Z, Mu XJ, O'Geen H, Ouyang Z, Patacsil D, Pei B, Raha D, Ramirez L, Reed B, Rozowsky J, Sboner A, Shi M, Sisu C, Slifer T, Witt H, Wu L, Xu X, Yan KK, Yang X, Yip KY, Zhang Z, Struhl K, Weissman SM, Gerstein M, Farnham PJ, Snyder M, Tenenbaum SA, Penalva LO, Doyle F, Karmakar S, Landt SG, Bhanvadia RR, Choudhury A, Domanus M, Ma L, Moran J, Patacsil D, Slifer T, Victorsen A, Yang X, Snyder M, Auer T, Centanin L, Eichenlaub M, Gruhl F, Heermann S, Hoeckendorf B, Inoue D, Kellner T, Kirchmaier S, Mueller C, Reinhardt R, Schertel L, Schneider S, Sinn R, Wittbrodt B, Wittbrodt J, Weng Z, Whitfield TW, Wang J, Collins PJ, Aldred SF, Trinklein ND, Partridge EC, Myers RM, Dekker J, Jain G, Lajoie BR, Sanyal A, Balasundaram G, Bates DL, Byron R, Canfield TK, Diegel MJ, Dunn D, Ebersol AK, Frum T, Garg K, Gist E, Hansen R, Boatman L, Haugen E, Humbert R, Jain G, Johnson AK, Johnson EM, Kutyavin TV, Lajoie BR, Lee K, Lotakis D, Maurano MT, Neph SJ, Neri FV, Nguyen ED, Qu H, Reynolds AP, Roach V, Rynes E, Sabo P, Sanchez ME, Sandstrom RS, Sanyal A, Shafer AO, Stergachis AB, Thomas S, Thurman RE, Vernot B, Vierstra J, Vong S, Wang H, Weaver MA, Yan Y, Zhang M, Akey JM, Bender M, Dorschner MO, Groudine M, MacCoss MJ, Navas P, Stamatoyannopoulos G, Kaul R, Dekker J, Stamatoyannopoulos JA, Dunham I, Beal K, Brazma A, Flicek P, Herrero J, Johnson N, Keefe D, Lukk M, Luscombe NM, Sobral D, Vaquerizas JM, Wilder SP, Batzoglou S, Sidow A, Hussami N, Kyriazopoulou-Panagiotopoulou S, Libbrecht MW, Schaub MA, Kundaje A, Hardison RC, Miller W, Giardine B, Harris RS, Wu W, Bickel PJ, Banfai B, Boley NP, Brown JB, Huang H, Li Q, Li JJ, Noble WS, Bilmes JA, Buske OJ, Hoffman MM, Sahu AD, Kharchenko PV, Park PJ, Baker D, Taylor J, Weng Z, Iyer S, Dong X, Greven M, Lin X, Wang J, Xi HS, Zhuang J, Gerstein M, Alexander RP, Balasubramanian S, Cheng C, Harmanci A, Lochovsky L, Min R, Mu XJ, Rozowsky J, Yan KK, Yip KY, Birney E., and Miotto, Benoit
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Encyclopedias as Topic ,[SDV]Life Sciences [q-bio] ,DNA Footprinting ,Genoma humà ,Binding Sites/genetics ,Histones/chemistry/metabolism ,0302 clinical medicine ,Exons/genetics ,ddc:576.5 ,0303 health sciences ,Multidisciplinary ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,[SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,DNA-Binding Proteins/metabolism ,region ,Chemistry ,Genetic Predisposition to Disease/genetics ,Genomics ,Polymorphism, Single Nucleotide/genetics ,[SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM] ,Neoplasms/genetics ,Chromatin ,Cell biology ,in vivo ,Genetic Variation/genetics ,030220 oncology & carcinogenesis ,Deoxyribonuclease I/metabolism ,Proteins/genetics ,transcription factor-binding ,chromosome conformation capture ,DNA Methylation/genetics ,Chromosomes, Human/genetics/metabolism ,Chromatin Immunoprecipitation ,Mammals/genetics ,DNA/genetics ,determinant ,Article ,03 medical and health sciences ,map ,Animals ,Humans ,Transcription Factors/metabolism ,Alleles ,mouse ,030304 developmental biology ,Transcription, Genetic/genetics ,Chromatin/genetics/metabolism ,Sequence Analysis, RNA ,human cell ,Molecular Sequence Annotation ,Regulatory Sequences, Nucleic Acid/genetics ,Promoter Regions, Genetic/genetics ,DNA binding site ,Genòmica ,Genome, Human/genetics ,chromatin ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Genètica ,Genome-Wide Association Study - Abstract
The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research. The Consortium is funded by grants from the NHGRI as follows: production grants: U54HG004570 (B. E. Bernstein); U01HG004695 (E. Birney); U54HG004563 (G. E. Crawford); U54HG004557 (T. R. Gingeras); U54HG004555 (T. J. Hubbard); U41HG004568 /n(W. J. Kent); U54HG004576 (R. M. Myers); U54HG004558 (M. Snyder);/nU54HG004592 (J. A. Stamatoyannopoulos). Pilot grants: R01HG003143 (J. Dekker); RC2HG005591 and R01HG003700 (M. C. Giddings); R01HG004456-03 (Y. Ruan); U01HG004571 (S. A. Tenenbaum); U01HG004561 (Z. Weng); RC2HG005679 (K. P. White). This project was supported in part by American Recovery and/nReinvestment Act (ARRA) funds from the NHGRI through grants U54HG004570, U54HG004563, U41HG004568, U54HG004592, R01HG003143, RC2HG005591,R01HG003541, U01HG004561, RC2HG005679andR01HG003988(L. Pennacchio). In addition, work from NHGRI Groups was supported by the Intramural Research/nProgram of the NHGRI (L. Elnitski, ZIAHG200323; E. H. Margulies, ZIAHG200341). Research in the Pennachio laboratory was performed at Lawrence Berkeley National Laboratory and at the United States Department of Energy Joint Genome Institute, Department of Energy Contract DE-AC02-05CH11231, University of California.
- Published
- 2012
11. Pineal region tumors: results of radiation therapy and indications for elective spinal irradiation. [/sup 60/Co; x ray]
- Author
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Groudine, M
- Published
- 1981
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12. Evaluation of fast neutron beam teletherapy of metastatic cervical adenopathy from squamous cell carinomas of the heat and neck region. [Comparison of efficacy and complications of fast and neutron and mixed (. gamma. + neutron) beam therapy]
- Author
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Groudine, M
- Published
- 1978
13. HP1α is a chromatin crosslinker that controls nuclear and mitotic chromosome mechanics.
- Author
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Strom AR, Biggs RJ, Banigan EJ, Wang X, Chiu K, Herman C, Collado J, Yue F, Ritland Politz JC, Tait LJ, Scalzo D, Telling A, Groudine M, Brangwynne CP, Marko JF, and Stephens AD
- Subjects
- Cell Line, Cell Nucleus chemistry, Chromobox Protein Homolog 5, Humans, Methylation, Cell Nucleus metabolism, Chromatin chemistry, Chromatin metabolism, Chromosomal Proteins, Non-Histone chemistry, Chromosomal Proteins, Non-Histone metabolism, Chromosomes chemistry, Chromosomes metabolism, Mitosis physiology
- Abstract
Chromatin, which consists of DNA and associated proteins, contains genetic information and is a mechanical component of the nucleus. Heterochromatic histone methylation controls nucleus and chromosome stiffness, but the contribution of heterochromatin protein HP1α (CBX5) is unknown. We used a novel HP1α auxin-inducible degron human cell line to rapidly degrade HP1α. Degradation did not alter transcription, local chromatin compaction, or histone methylation, but did decrease chromatin stiffness. Single-nucleus micromanipulation reveals that HP1α is essential to chromatin-based mechanics and maintains nuclear morphology, separate from histone methylation. Further experiments with dimerization-deficient HP1α
I165E indicate that chromatin crosslinking via HP1α dimerization is critical, while polymer simulations demonstrate the importance of chromatin-chromatin crosslinkers in mechanics. In mitotic chromosomes, HP1α similarly bolsters stiffness while aiding in mitotic alignment and faithful segregation. HP1α is therefore a critical chromatin-crosslinking protein that provides mechanical strength to chromosomes and the nucleus throughout the cell cycle and supports cellular functions., Competing Interests: AS, RB, EB, XW, KC, CH, JC, FY, JR, LT, DS, AT, MG, CB, JM, AS No competing interests declared, (© 2021, Strom et al.)- Published
- 2021
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14. Tissue context determines the penetrance of regulatory DNA variation.
- Author
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Halow JM, Byron R, Hogan MS, Ordoñez R, Groudine M, Bender MA, Stamatoyannopoulos JA, and Maurano MT
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- Alleles, Animals, Binding Sites genetics, Chromatin genetics, Chromatin metabolism, Chromosome Mapping, DNA metabolism, Female, Gene Expression Regulation, Genetic Variation, Genome, Human, Humans, Hybridization, Genetic, Male, Mice, Mice, 129 Strain, Mice, Inbred C3H, Mice, Inbred C57BL, Organ Specificity genetics, Penetrance, Regulatory Sequences, Nucleic Acid, Transcription Factors metabolism, DNA genetics
- Abstract
Functional assessment of disease-associated sequence variation at non-coding regulatory elements is complicated by their high degree of context sensitivity to both the local chromatin and nuclear environments. Allelic profiling of DNA accessibility across individuals has shown that only a select minority of sequence variation affects transcription factor (TF) occupancy, yet low sequence diversity in human populations means that no experimental assessment is available for the majority of disease-associated variants. Here we describe high-resolution in vivo maps of allelic DNA accessibility in liver, kidney, lung and B cells from 5 increasingly diverged strains of F1 hybrid mice. The high density of heterozygous sites in these hybrids enables precise quantification of effect size and cell-type specificity for hundreds of thousands of variants throughout the mouse genome. We show that chromatin-altering variants delineate characteristic sensitivity profiles for hundreds of TF motifs. We develop a compendium of TF-specific sensitivity profiles accounting for genomic context effects. Finally, we link maps of allelic accessibility to allelic transcript levels in the same samples. This work provides a foundation for quantitative prediction of cell-type specific effects of non-coding variation on TF activity, which will facilitate both fine-mapping and systems-level analyses of common disease-associated variation in human genomes.
- Published
- 2021
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15. The redundancy of the mammalian heterochromatic compartment.
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Politz JCR, Scalzo D, and Groudine M
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- Animals, Cell Nucleus genetics, Euchromatin genetics, Genomic Instability genetics, Mammals genetics, Base Sequence genetics, Chromatin genetics, Heterochromatin genetics
- Abstract
Two chromatin compartments are present in most mammalian cells; the first contains primarily euchromatic, early replicating chromatin and the second, primarily late-replicating heterochromatin, which is the subject of this review. Heterochromatin is concentrated in three intranuclear regions: the nuclear periphery, the perinucleolar space and in pericentromeric bodies. We review recent evidence demonstrating that the heterochromatic compartment is critically involved in global nuclear organization and the maintenance of genome stability, and discuss models regarding how this compartment is formed and maintained. We also evaluate our understanding of how heterochromatic sequences (herein named heterochromatic associated regions (HADs)) might be tethered within these regions and review experiments that reveal the stochastic nature of individual HAD positioning within the compartment. These investigations suggest a substantial level of functional redundancy within the heterochromatic compartment., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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16. Distinct Activities of Myf5 and MyoD Indicate Separate Roles in Skeletal Muscle Lineage Specification and Differentiation.
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Conerly ML, Yao Z, Zhong JW, Groudine M, and Tapscott SJ
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- Animals, Gene Expression Regulation, Developmental physiology, Mice, Muscle Proteins metabolism, Transcriptional Activation physiology, Cell Differentiation physiology, Cell Lineage, Muscle, Skeletal cytology, Muscle, Skeletal metabolism, MyoD Protein metabolism, Myogenic Regulatory Factor 5 metabolism
- Abstract
Most transcription factor families contain highly related paralogs generated by gene duplication, and functional divergence is generally accomplished by activation of distinct sets of genes by each member. Here we compare the molecular functions of Myf5 and MyoD, two highly related bHLH transcription factors that regulate skeletal muscle specification and differentiation. We find that MyoD and Myf5 bind the same sites genome-wide but have distinct functions: Myf5 induces histone acetylation without Pol II recruitment or robust gene activation, whereas MyoD induces histone acetylation, recruits Pol II, and robustly activates gene transcription. Therefore, the initial specification of the muscle lineage by Myf5 occurs without significant induction of gene transcription. Transcription of the skeletal muscle program is then achieved by the subsequent expression of MyoD, which binds to the same sites as Myf5, indicating that each factor regulates distinct steps in gene initiation and transcription at a shared set of binding sites., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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17. Prelamin A processing, accumulation and distribution in normal cells and laminopathy disorders.
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Casasola A, Scalzo D, Nandakumar V, Halow J, Recillas-Targa F, Groudine M, and Rincón-Arano H
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- Animals, HeLa Cells, Humans, Lamin Type A genetics, Membrane Proteins genetics, Metalloendopeptidases genetics, Mice, Mice, Knockout, Progeria genetics, Protein Transport, Lamin Type A metabolism, Membrane Proteins metabolism, Metalloendopeptidases metabolism, Mutation, Progeria metabolism, Protein Prenylation
- Abstract
Lamin A is part of a complex structural meshwork located beneath the nuclear envelope and is involved in both structural support and the regulation of gene expression. Lamin A is initially expressed as prelamin A, which contains an extended carboxyl terminus that undergoes a series of post-translational modifications and subsequent cleavage by the endopeptidase ZMPSTE24 to generate lamin A. To facilitate investigations of the role of this cleavage in normal and disease states, we developed a monoclonal antibody (PL-1C7) that specifically recognizes prelamin A at the intact ZMPSTE24 cleavage site, ensuring prelamin A detection exclusively. Importantly, PL-1C7 can be used to determine prelamin A localization and accumulation in cells where lamin A is highly expressed without the use of exogenous fusion proteins. Our results show that unlike mature lamin A, prelamin A accumulates as discrete and localized foci at the nuclear periphery. Furthermore, whereas treatment with farnesylation inhibitors of cells overexpressing a GFP-prelamin A fusion protein results in the formation of large nucleoplasmic clumps, these aggregates are not observed upon similar treatment of cells expressing endogenous prelamin A or in cells lacking ZMPSTE24 expression and/or activity. Finally, we show that specific laminopathy-associated mutations exhibit both positive and negative effects on prelamin A accumulation, indicating that these mutations affect prelamin A processing efficiency in different manners.
- Published
- 2016
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18. Olfactory receptor genes expressed in distinct lineages are sequestered in different nuclear compartments.
- Author
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Yoon KH, Ragoczy T, Lu Z, Kondoh K, Kuang D, Groudine M, and Buck LB
- Subjects
- Alleles, Animals, Cell Lineage, Chromosomes, Artificial, Bacterial, Crosses, Genetic, Female, Gene Expression Regulation, Heterochromatin metabolism, In Situ Hybridization, In Situ Hybridization, Fluorescence, Lamin Type A metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Mutation, Odorants, Olfactory Mucosa metabolism, Olfactory Receptor Neurons physiology, Sensory Receptor Cells metabolism, Smell physiology, Cell Nucleus metabolism, Receptors, Odorant genetics
- Abstract
The olfactory system translates a vast array of volatile chemicals into diverse odor perceptions and innate behaviors. Odor detection in the mouse nose is mediated by 1,000 different odorant receptors (ORs) and 14 trace amine-associated receptors (TAARs). ORs are used in a combinatorial manner to encode the unique identities of myriad odorants. However, some TAARs appear to be linked to innate responses, raising questions about regulatory mechanisms that might segregate OR and TAAR expression in appropriate subsets of olfactory sensory neurons (OSNs). Here, we report that OSNs that express TAARs comprise at least two subsets that are biased to express TAARs rather than ORs. The two subsets are further biased in Taar gene choice and their distribution within the sensory epithelium, with each subset preferentially expressing a subgroup of Taar genes within a particular spatial domain in the epithelium. Our studies reveal one mechanism that may regulate the segregation of Olfr (OR) and Taar expression in different OSNs: the sequestration of Olfr and Taar genes in different nuclear compartments. Although most Olfr genes colocalize near large central heterochromatin aggregates in the OSN nucleus, Taar genes are located primarily at the nuclear periphery, coincident with a thin rim of heterochromatin. Taar-expressing OSNs show a shift of one Taar allele away from the nuclear periphery. Furthermore, examination of hemizygous mice with a single Taar allele suggests that the activation of a Taar gene is accompanied by an escape from the peripheral repressive heterochromatin environment to a more permissive interior chromatin environment.
- Published
- 2015
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19. Wash interacts with lamin and affects global nuclear organization.
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Verboon JM, Rincon-Arano H, Werwie TR, Delrow JJ, Scalzo D, Nandakumar V, Groudine M, and Parkhurst SM
- Subjects
- Animals, Animals, Genetically Modified, Cell Nucleus genetics, Cell Nucleus ultrastructure, Drosophila Proteins genetics, Drosophila melanogaster genetics, Drosophila melanogaster metabolism, Drosophila melanogaster ultrastructure, Female, Gene Knockdown Techniques, Genes, Insect, Heterochromatin genetics, Heterochromatin metabolism, Lamins genetics, Male, Mutation, Vesicular Transport Proteins genetics, Cell Nucleus metabolism, Drosophila Proteins metabolism, Lamins metabolism, Vesicular Transport Proteins metabolism
- Abstract
The cytoplasmic functions of Wiskott-Aldrich syndrome family (WAS) proteins are well established and include roles in cytoskeleton reorganization and membrane-cytoskeletal interactions important for membrane/vesicle trafficking, morphogenesis, immune response, and signal transduction. Misregulation of these proteins is associated with immune deficiency and metastasis [1-4]. Cytoplasmic WAS proteins act as effectors of Rho family GTPases and polymerize branched actin through the Arp2/3 complex [1, 5]. Previously, we identified Drosophila washout (wash) as a new member of the WAS family with essential cytoplasmic roles in early development [6, 7]. Studies in mammalian cells and Dictyostelium suggest that WASH functions primarily in a multiprotein complex that regulates endosome shape and trafficking in an Arp2/3-dependent manner [8-11]. However, roles for classically cytoplasmic proteins in the nucleus are beginning to emerge, in particular, as participants in the regulation of gene expression [12, 13]. Here, we show that Drosophila Wash is present in the nucleus, where it plays a key role in global nuclear organization. wash mutant and knockdown nuclei disrupt subnuclear structures/organelles and exhibit the abnormal wrinkled morphology reminiscent of those observed in diverse laminopathies [14-16]. We find that nuclear Wash interacts with B-type Lamin (Lamin Dm0), and, like Lamin, Wash associates with constitutive heterochromatin. Wash knockdown increases chromatin accessibility of repressive compartments and results in a global redistribution of repressive histone modifications. Thus, our results reveal a novel role for Wash in modulating nucleus morphology and in the organization of both chromatin and non-chromatin nuclear sub-structures., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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20. An acetyl-methyl switch drives a conformational change in p53.
- Author
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Tong Q, Mazur SJ, Rincon-Arano H, Rothbart SB, Kuznetsov DM, Cui G, Liu WH, Gete Y, Klein BJ, Jenkins L, Mer G, Kutateladze AG, Strahl BD, Groudine M, Appella E, and Kutateladze TG
- Subjects
- Crystallography, X-Ray, DNA Damage physiology, Humans, Lysine metabolism, Magnetic Resonance Spectroscopy, Protein Conformation, DNA Methylation genetics, Ligands, Models, Molecular, Protein Processing, Post-Translational genetics, Tumor Suppressor Protein p53 chemistry, Tumor Suppressor Protein p53 metabolism
- Abstract
Individual posttranslational modifications (PTMs) of p53 mediate diverse p53-dependent responses; however, much less is known about the combinatorial action of adjacent modifications. Here, we describe crosstalk between the early DNA damage response mark p53K382me2 and the surrounding PTMs that modulate binding of p53 cofactors, including 53BP1 and p300. The 1.8 Å resolution crystal structure of the tandem Tudor domain (TTD) of 53BP1 in complex with p53 peptide acetylated at K381 and dimethylated at K382 (p53K381acK382me2) reveals that the dual PTM induces a conformational change in p53. The α-helical fold of p53K381acK382me2 positions the side chains of R379, K381ac, and K382me2 to interact with TTD concurrently, reinforcing a modular design of double PTM mimetics. Biochemical and nuclear magnetic resonance analyses show that other surrounding PTMs, including phosphorylation of serine/threonine residues of p53, affect association with TTD. Our findings suggest a novel PTM-driven conformation switch-like mechanism that may regulate p53 interactions with binding partners., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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21. Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution.
- Author
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Vierstra J, Rynes E, Sandstrom R, Zhang M, Canfield T, Hansen RS, Stehling-Sun S, Sabo PJ, Byron R, Humbert R, Thurman RE, Johnson AK, Vong S, Lee K, Bates D, Neri F, Diegel M, Giste E, Haugen E, Dunn D, Wilken MS, Josefowicz S, Samstein R, Chang KH, Eichler EE, De Bruijn M, Reh TA, Skoultchi A, Rudensky A, Orkin SH, Papayannopoulou T, Treuting PM, Selleri L, Kaul R, Groudine M, Bender MA, and Stamatoyannopoulos JA
- Subjects
- Animals, Base Sequence, Deoxyribonuclease I, Genome, Human, Humans, Mice, Restriction Mapping, Conserved Sequence, DNA genetics, Evolution, Molecular, Regulatory Sequences, Nucleic Acid genetics, Transcription Factors metabolism
- Abstract
To study the evolutionary dynamics of regulatory DNA, we mapped >1.3 million deoxyribonuclease I-hypersensitive sites (DHSs) in 45 mouse cell and tissue types, and systematically compared these with human DHS maps from orthologous compartments. We found that the mouse and human genomes have undergone extensive cis-regulatory rewiring that combines branch-specific evolutionary innovation and loss with widespread repurposing of conserved DHSs to alternative cell fates, and that this process is mediated by turnover of transcription factor (TF) recognition elements. Despite pervasive evolutionary remodeling of the location and content of individual cis-regulatory regions, within orthologous mouse and human cell types the global fraction of regulatory DNA bases encoding recognition sites for each TF has been strictly conserved. Our findings provide new insights into the evolutionary forces shaping mammalian regulatory DNA landscapes., (Copyright © 2014, American Association for the Advancement of Science.)
- Published
- 2014
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22. Conservation of trans-acting circuitry during mammalian regulatory evolution.
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Stergachis AB, Neph S, Sandstrom R, Haugen E, Reynolds AP, Zhang M, Byron R, Canfield T, Stelhing-Sun S, Lee K, Thurman RE, Vong S, Bates D, Neri F, Diegel M, Giste E, Dunn D, Vierstra J, Hansen RS, Johnson AK, Sabo PJ, Wilken MS, Reh TA, Treuting PM, Kaul R, Groudine M, Bender MA, Borenstein E, and Stamatoyannopoulos JA
- Subjects
- Animals, DNA Footprinting, Gene Expression Regulation, Developmental genetics, Gene Regulatory Networks genetics, Humans, Mice, Conserved Sequence genetics, Evolution, Molecular, Mammals genetics, Regulatory Sequences, Nucleic Acid genetics, Transcription Factors genetics, Transcription Factors metabolism
- Abstract
The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining ∼8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is ∼95% similar with that derived from human TF footprints. However, only ∼20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity.
- Published
- 2014
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23. Nucleolar tethering mediates pairing between the IgH and Myc loci.
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Strongin DE, Groudine M, and Politz JC
- Subjects
- Animals, B-Lymphocytes pathology, Burkitt Lymphoma genetics, Burkitt Lymphoma pathology, Humans, Immunoglobulin Heavy Chains genetics, Mice, Chromosomes genetics, Genes, myc genetics, Nucleolus Organizer Region genetics, Translocation, Genetic genetics
- Abstract
Gene loci on different chromosomes can preferentially colocalize in the cell nucleus. However, many of the mechanisms mediating this spatial proximity remain to be elucidated. The IgH locus on Chromosome 12 and the Myc locus on Chromosome 15 are a well-studied model for gene colocalization in murine B cells, where the two loci are positioned in close proximity at a higher than expected frequency. These gene loci are also partners in the chromosomal translocation that causes murine plasmacytoma and Burkitt's lymphoma. Because both Chromosome 12 and Chromosome 15 carry nucleolar organizer regions (NORs) in the most commonly studied mouse strains, we hypothesized that NOR-mediated tethering of the IgH and Myc loci to shared nucleoli could serve as a mechanism to drive IgH:Myc colocalization. Using mouse strains that naturally carry nucleolar organizer regions (NORs) on different sets of chromosomes, we establish that IgH and Myc are positioned proximal to nucleoli in a NOR dependent manner and show that their joint association with nucleoli significantly increases the frequency of IgH and Myc pairing. Thus we demonstrate that simple nucleolar tethering can increase the colocalization frequency of genes on NOR-bearing chromosomes.
- Published
- 2014
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24. The nucleosomal barrier to promoter escape by RNA polymerase II is overcome by the chromatin remodeler Chd1.
- Author
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Skene PJ, Hernandez AE, Groudine M, and Henikoff S
- Subjects
- Adenosine Triphosphatases metabolism, Amino Acid Sequence, DNA-Binding Proteins chemistry, Molecular Sequence Data, Sequence Homology, Amino Acid, DNA-Binding Proteins metabolism, Nucleosomes metabolism, Promoter Regions, Genetic, RNA Polymerase II metabolism
- Abstract
RNA polymerase II (PolII) transcribes RNA within a chromatin context, with nucleosomes acting as barriers to transcription. Despite these barriers, transcription through chromatin in vivo is highly efficient, suggesting the existence of factors that overcome this obstacle. To increase the resolution obtained by standard chromatin immunoprecipitation, we developed a novel strategy using micrococcal nuclease digestion of cross-linked chromatin. We find that the chromatin remodeler Chd1 is recruited to promoter proximal nucleosomes of genes undergoing active transcription, where Chd1 is responsible for the vast majority of PolII-directed nucleosome turnover. The expression of a dominant negative form of Chd1 results in increased stalling of PolII past the entry site of the promoter proximal nucleosomes. We find that Chd1 evicts nucleosomes downstream of the promoter in order to overcome the nucleosomal barrier and enable PolII promoter escape, thus providing mechanistic insight into the role of Chd1 in transcription and pluripotency. DOI: http://dx.doi.org/10.7554/eLife.02042.001.
- Published
- 2014
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25. The histone-H3K4-specific demethylase KDM5B binds to its substrate and product through distinct PHD fingers.
- Author
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Klein BJ, Piao L, Xi Y, Rincon-Arano H, Rothbart SB, Peng D, Wen H, Larson C, Zhang X, Zheng X, Cortazar MA, Peña PV, Mangan A, Bentley DL, Strahl BD, Groudine M, Li W, Shi X, and Kutateladze TG
- Subjects
- Amino Acid Sequence, Binding Sites, Breast Neoplasms genetics, Breast Neoplasms metabolism, Cell Line, Tumor, Chromatin Assembly and Disassembly, Histone Deacetylase 1 metabolism, Humans, Jumonji Domain-Containing Histone Demethylases chemistry, Jumonji Domain-Containing Histone Demethylases genetics, Mi-2 Nucleosome Remodeling and Deacetylase Complex metabolism, Molecular Sequence Data, Nuclear Proteins chemistry, Nuclear Proteins genetics, Protein Binding, Repressor Proteins chemistry, Repressor Proteins genetics, Gene Expression Regulation, Neoplastic, Histones metabolism, Jumonji Domain-Containing Histone Demethylases metabolism, Nuclear Proteins metabolism, Repressor Proteins metabolism
- Abstract
The histone lysine demethylase KDM5B regulates gene transcription and cell differentiation and is implicated in carcinogenesis. It contains multiple conserved chromatin-associated domains, including three PHD fingers of unknown function. Here, we show that the first and third, but not the second, PHD fingers of KDM5B possess histone binding activities. The PHD1 finger is highly specific for unmodified histone H3 (H3K4me0), whereas the PHD3 finger shows preference for the trimethylated histone mark H3K4me3. RNA-seq analysis indicates that KDM5B functions as a transcriptional repressor for genes involved in inflammatory responses, cell proliferation, adhesion, and migration. Biochemical analysis reveals that KDM5B associates with components of the nucleosome remodeling and deacetylase (NuRD) complex and may cooperate with the histone deacetylase 1 (HDAC1) in gene repression. KDM5B is downregulated in triple-negative breast cancer relative to estrogen-receptor-positive breast cancer. Overexpression of KDM5B in the MDA-MB 231 breast cancer cells suppresses cell migration and invasion, and the PHD1-H3K4me0 interaction is essential for inhibiting migration. These findings highlight tumor-suppressive functions of KDM5B in triple-negative breast cancer cells and suggest a multivalent mechanism for KDM5B-mediated transcriptional regulation., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
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- View/download PDF
26. Functional redundancy in the nuclear compartmentalization of the late-replicating genome.
- Author
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Ragoczy T, Telling A, Scalzo D, Kooperberg C, and Groudine M
- Subjects
- Cell Line, Cell Nucleus ultrastructure, Chromosomes genetics, Euchromatin genetics, Genome, Human, Heterochromatin ultrastructure, Humans, In Situ Hybridization, Fluorescence, Cell Compartmentation genetics, Cell Nucleus genetics, DNA Replication genetics, Heterochromatin genetics
- Abstract
The eukaryotic nucleus is structurally and functionally organized, as reflected in the distribution of its protein and DNA components. The genome itself is segregated into euchromatin and heterochromatin that replicate in a distinct spatio-temporal manner. We used a combination of fluorescence in situ hybridization (FISH) and DamID to investigate the localization of the early and late replicating components of the genome in a lymphoblastoid cell background. Our analyses revealed that the bulk of late replicating chromatin localizes to the nuclear peripheral heterochromatin (PH) in a chromosome size and gene density dependent manner. Late replicating DNA on small chromosomes exhibits a much lower tendency to localize to PH and tends to associate with alternate repressive subcompartments such as pericentromeric (PCH) and perinucleolar heterochromatin (PNH). Furthermore, multicolor FISH analysis revealed that late replicating loci, particularly on the smaller chromosomes, may associate with any of these 3 repressive subcompartments, including more than one at the same time. These results suggest a functional equivalence or redundancy among the 3 subcompartments. Consistent with this notion, disruption of nucleoli resulted in an increased association of late replicating loci with peripheral heterochromatin. Our analysis reveals that rather than considering the morphologically distinct PH, PCH and PNH as individual subcompartments, they should be considered in aggregate as a functional compartment for late replicating chromatin.
- Published
- 2014
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27. Dido3 PHD modulates cell differentiation and division.
- Author
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Gatchalian J, Fütterer A, Rothbart SB, Tong Q, Rincon-Arano H, Sánchez de Diego A, Groudine M, Strahl BD, Martínez-A C, van Wely KH, and Kutateladze TG
- Subjects
- Amino Acid Sequence, Animals, Binding Sites, Cell Line, Tumor, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Embryonic Stem Cells cytology, Embryonic Stem Cells metabolism, Embryonic Stem Cells physiology, Histones chemistry, Histones metabolism, Humans, Mice, Molecular Docking Simulation, Molecular Sequence Data, Mutation, Phosphorylation, Protein Structure, Tertiary, Spindle Apparatus metabolism, Transcription Factors genetics, Transcription Factors metabolism, Cell Differentiation, DNA-Binding Proteins chemistry, Mitosis, Transcription Factors chemistry
- Abstract
Death Inducer Obliterator 3 (Dido3) is implicated in the maintenance of stem cell genomic stability and tumorigenesis. Here, we show that Dido3 regulates the expression of stemness genes in embryonic stem cells through its plant homeodomain (PHD) finger. Binding of Dido3 PHD to histone H3K4me3 is disrupted by threonine phosphorylation that triggers Dido3 translocation from chromatin to the mitotic spindle. The crystal structure of Dido3 PHD in complex with H3K4me3 reveals an atypical aromatic-cage-like binding site that contains a histidine residue. Biochemical, structural, and mutational analyses of the binding mechanism identified the determinants of specificity and affinity and explained the inability of homologous PHF3 to bind H3K4me3. Together, our findings reveal a link between the transcriptional control in embryonic development and regulation of cell division., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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28. Molecular basis for chromatin binding and regulation of MLL5.
- Author
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Ali M, Rincón-Arano H, Zhao W, Rothbart SB, Tong Q, Parkhurst SM, Strahl BD, Deng LW, Groudine M, and Kutateladze TG
- Subjects
- Amino Acid Sequence, DNA-Binding Proteins chemistry, Humans, Models, Molecular, Molecular Sequence Data, Phosphorylation, Protein Binding, Protein Conformation, Sequence Homology, Amino Acid, Chromatin metabolism, DNA-Binding Proteins metabolism
- Abstract
The human mixed-lineage leukemia 5 (MLL5) protein mediates hematopoietic cell homeostasis, cell cycle, and survival; however, the molecular basis underlying MLL5 activities remains unknown. Here, we show that MLL5 is recruited to gene-rich euchromatic regions via the interaction of its plant homeodomain finger with the histone mark H3K4me3. The 1.48-Å resolution crystal structure of MLL5 plant homeodomain in complex with the H3K4me3 peptide reveals a noncanonical binding mechanism, whereby K4me3 is recognized through a single aromatic residue and an aspartate. The binding induces a unique His-Asp swapping rearrangement mediated by a C-terminal α-helix. Phosphorylation of H3T3 and H3T6 abrogates the association with H3K4me3 in vitro and in vivo, releasing MLL5 from chromatin in mitosis. This regulatory switch is conserved in the Drosophila ortholog of MLL5, UpSET, and suggests the developmental control for targeting of H3K4me3. Together, our findings provide first insights into the molecular basis for the recruitment, exclusion, and regulation of MLL5 at chromatin.
- Published
- 2013
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29. UpSET-ting the balance: modulating open chromatin features in metazoan genomes.
- Author
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Rincon-Arano H, Parkhurst SM, and Groudine M
- Subjects
- Animals, Female, Drosophila Proteins metabolism, Drosophila melanogaster metabolism, Histone Deacetylases metabolism, Promoter Regions, Genetic
- Abstract
Appropriate gene expression relies on the sophisticated interplay between genetic and epigenetic factors. Histone acetylation and an open chromatin configuration are key features of transcribed regions and are mainly present around active promoters. Our recent identification of the SET-domain containing protein UpSET established a new functional link between the modulation of open chromatin features and active recruitment of well-known co-repressors in metazoans. Structurally, the SET domain of UpSET resembles H3K4 and H3K36 methyltransferases; however, it is does not confer histone methyltransferase activity. Rather than methylating histones to regulate gene expression like other SET domain-containing proteins, UpSET fine-tunes transcription by modulating the chromatin structure around active promoters resulting in suppression of expression of off-target genes or nearby repetitive elements. Chromatin modulation by UpSET occurs in part through its interaction with histone deacetylases. Here, we discuss the different scenarios in which UpSET could play key roles in modulating gene expression.
- Published
- 2013
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- View/download PDF
30. When untethered, something silent inside comes.
- Author
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Politz JC, Ragoczy T, and Groudine M
- Subjects
- Animals, Heterochromatin metabolism, Lamin Type A metabolism, Muscle Development, Myoblasts metabolism, Receptors, Cytoplasmic and Nuclear metabolism
- Abstract
Heterochromatin usually is sequestered near the periphery and the nucleoli in mammalian nuclei. However, in terminally differentiated retinal rod cells of nocturnal mammals, heterochromatin instead accumulates in the interior, to give a so-called inside-out nuclear architecture. Solovei et al. now reports that in most cells, the lamin B receptor mediates peripheral localization early during development and that lamin A/C then takes over this tethering function during terminal differentiation. Furthermore, they show that the unique architecture of the nocturnal animal rod cell is caused by the absence of both tethers and can be phenocopied in LBR/lamin A/C double knockouts.
- Published
- 2013
- Full Text
- View/download PDF
31. Something silent this way forms: the functional organization of the repressive nuclear compartment.
- Author
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Politz JC, Scalzo D, and Groudine M
- Subjects
- Animals, Cell Nucleus metabolism, Gene Silencing, Heterochromatin metabolism, Humans, Transcription, Genetic, Cell Nucleus genetics, Heterochromatin genetics
- Abstract
The repressive compartment of the nucleus is comprised primarily of telomeric and centromeric regions, the silent portion of ribosomal RNA genes, the majority of transposable element repeats, and facultatively repressed genes specific to different cell types. This compartment localizes into three main regions: the peripheral heterochromatin, perinucleolar heterochromatin, and pericentromeric heterochromatin. Both chromatin remodeling proteins and transcription of noncoding RNAs are involved in maintenance of repression in these compartments. Global reorganization of the repressive compartment occurs at each cell division, during early development, and during terminal differentiation. Differential action of chromatin remodeling complexes and boundary element looping activities are involved in mediating these organizational changes. We discuss the evidence that heterochromatin formation and compartmentalization may drive nuclear organization.
- Published
- 2013
- Full Text
- View/download PDF
32. UpSET recruits HDAC complexes and restricts chromatin accessibility and acetylation at promoter regions.
- Author
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Rincon-Arano H, Halow J, Delrow JJ, Parkhurst SM, and Groudine M
- Subjects
- Acetylation, Animals, Chromatin, Drosophila Proteins chemistry, Drosophila Proteins genetics, Female, Gene Knockdown Techniques, Histone-Lysine N-Methyltransferase genetics, Histone-Lysine N-Methyltransferase metabolism, Mice, Mutation, Drosophila Proteins metabolism, Drosophila melanogaster metabolism, Histone Deacetylases metabolism, Promoter Regions, Genetic
- Abstract
Developmental gene expression results from the orchestrated interplay between genetic and epigenetic mechanisms. Here, we describe upSET, a transcriptional regulator encoding a SET domain-containing protein recruited to active and inducible genes in Drosophila. However, unlike other Drosophila SET proteins associated with gene transcription, UpSET is part of an Rpd3/Sin3-containing complex that restricts chromatin accessibility and histone acetylation to promoter regions. In the absence of UpSET, active chromatin marks and chromatin accessibility increase and spread to genic and flanking regions due to destabilization of the histone deacetylase complex. Consistent with this, transcriptional noise increases, as manifest by activation of repetitive elements and off-target genes. Interestingly, upSET mutant flies are female sterile due to upregulation of key components of Notch signaling during oogenesis. Thus UpSET defines a class of metazoan transcriptional regulators required to fine tune transcription by preventing the spread of active chromatin., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
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33. An expansive human regulatory lexicon encoded in transcription factor footprints.
- Author
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Neph S, Vierstra J, Stergachis AB, Reynolds AP, Haugen E, Vernot B, Thurman RE, John S, Sandstrom R, Johnson AK, Maurano MT, Humbert R, Rynes E, Wang H, Vong S, Lee K, Bates D, Diegel M, Roach V, Dunn D, Neri J, Schafer A, Hansen RS, Kutyavin T, Giste E, Weaver M, Canfield T, Sabo P, Zhang M, Balasundaram G, Byron R, MacCoss MJ, Akey JM, Bender MA, Groudine M, Kaul R, and Stamatoyannopoulos JA
- Subjects
- DNA Methylation, DNA-Binding Proteins metabolism, Deoxyribonuclease I metabolism, Genomic Imprinting, Genomics, Humans, Polymorphism, Single Nucleotide genetics, Transcription Initiation Site, DNA genetics, DNA Footprinting, Encyclopedias as Topic, Genome, Human genetics, Molecular Sequence Annotation, Regulatory Sequences, Nucleic Acid genetics, Transcription Factors metabolism
- Abstract
Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNase I, leaving nucleotide-resolution footprints. Using genomic DNase I footprinting across 41 diverse cell and tissue types, we detected 45 million transcription factor occupancy events within regulatory regions, representing differential binding to 8.4 million distinct short sequence elements. Here we show that this small genomic sequence compartment, roughly twice the size of the exome, encodes an expansive repertoire of conserved recognition sequences for DNA-binding proteins that nearly doubles the size of the human cis-regulatory lexicon. We find that genetic variants affecting allelic chromatin states are concentrated in footprints, and that these elements are preferentially sheltered from DNA methylation. High-resolution DNase I cleavage patterns mirror nucleotide-level evolutionary conservation and track the crystallographic topography of protein-DNA interfaces, indicating that transcription factor structure has been evolutionarily imprinted on the human genome sequence. We identify a stereotyped 50-base-pair footprint that precisely defines the site of transcript origination within thousands of human promoters. Finally, we describe a large collection of novel regulatory factor recognition motifs that are highly conserved in both sequence and function, and exhibit cell-selective occupancy patterns that closely parallel major regulators of development, differentiation and pluripotency.
- Published
- 2012
- Full Text
- View/download PDF
34. An encyclopedia of mouse DNA elements (Mouse ENCODE).
- Author
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Stamatoyannopoulos JA, Snyder M, Hardison R, Ren B, Gingeras T, Gilbert DM, Groudine M, Bender M, Kaul R, Canfield T, Giste E, Johnson A, Zhang M, Balasundaram G, Byron R, Roach V, Sabo PJ, Sandstrom R, Stehling AS, Thurman RE, Weissman SM, Cayting P, Hariharan M, Lian J, Cheng Y, Landt SG, Ma Z, Wold BJ, Dekker J, Crawford GE, Keller CA, Wu W, Morrissey C, Kumar SA, Mishra T, Jain D, Byrska-Bishop M, Blankenberg D, Lajoie BR, Jain G, Sanyal A, Chen KB, Denas O, Taylor J, Blobel GA, Weiss MJ, Pimkin M, Deng W, Marinov GK, Williams BA, Fisher-Aylor KI, Desalvo G, Kiralusha A, Trout D, Amrhein H, Mortazavi A, Edsall L, McCleary D, Kuan S, Shen Y, Yue F, Ye Z, Davis CA, Zaleski C, Jha S, Xue C, Dobin A, Lin W, Fastuca M, Wang H, Guigo R, Djebali S, Lagarde J, Ryba T, Sasaki T, Malladi VS, Cline MS, Kirkup VM, Learned K, Rosenbloom KR, Kent WJ, Feingold EA, Good PJ, Pazin M, Lowdon RF, and Adams LB
- Subjects
- Animals, Genome, Genome, Human, Humans, Internet, Databases, Nucleic Acid, Genomics, Mice genetics, Molecular Sequence Annotation
- Abstract
To complement the human Encyclopedia of DNA Elements (ENCODE) project and to enable a broad range of mouse genomics efforts, the Mouse ENCODE Consortium is applying the same experimental pipelines developed for human ENCODE to annotate the mouse genome.
- Published
- 2012
- Full Text
- View/download PDF
35. The hypersensitive sites of the murine β-globin locus control region act independently to affect nuclear localization and transcriptional elongation.
- Author
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Bender MA, Ragoczy T, Lee J, Byron R, Telling A, Dean A, and Groudine M
- Subjects
- Animals, Erythroid Cells metabolism, Gene Deletion, Gene Expression Regulation, Developmental physiology, Mice, Mice, Transgenic, RNA, Messenger genetics, beta-Globins metabolism, Cell Nucleus metabolism, Locus Control Region genetics, Nucleoplasmins metabolism, Transcription, Genetic physiology, beta-Globins genetics
- Abstract
The β-globin locus control region (LCR) is necessary for high-level β-globin gene transcription and differentiation-dependent relocation of the β-globin locus from the nuclear periphery to the central nucleoplasm and to foci of hyperphosphorylated Pol II "transcription factories" (TFys). To determine the contribution of individual LCR DNaseI hypersensitive sites (HSs) to transcription and nuclear location, in the present study, we compared β-globin gene activity and location in erythroid cells derived from mice with deletions of individual HSs, deletions of 2 HSs, and deletion of the whole LCR and found all of the HSs had a similar spectrum of activities, albeit to different degrees. Each HS acts as an independent module to activate expression in an additive manner, and this is correlated with relocation away from the nuclear periphery. In contrast, HSs have redundant activities with respect to association with TFys and the probability that an allele is actively transcribed, as measured by primary RNA transcript FISH. The limiting effect on RNA levels occurs after β-globin genes associate with TFys, at which time HSs contribute to the amount of RNA arising from each burst of transcription by stimulating transcriptional elongation.
- Published
- 2012
- Full Text
- View/download PDF
36. What can systems theory of networks offer to biology?
- Author
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Rajapakse I, Groudine M, and Mesbahi M
- Subjects
- Cell Differentiation physiology, Computational Biology, Humans, Signal Transduction, Models, Biological, Systems Theory
- Published
- 2012
- Full Text
- View/download PDF
37. Dynamics and control of state-dependent networks for probing genomic organization.
- Author
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Rajapakse I, Groudine M, and Mesbahi M
- Subjects
- Animals, Cell Differentiation physiology, Feedback, Physiological, GATA1 Transcription Factor genetics, GATA1 Transcription Factor metabolism, Hematopoiesis genetics, Hematopoiesis physiology, Humans, Models, Biological, MyoD Protein genetics, MyoD Protein metabolism, Cell Differentiation genetics, Gene Regulatory Networks, Models, Genetic
- Abstract
A state-dependent dynamic network is a collection of elements that interact through a network, whose geometry evolves as the state of the elements changes over time. The genome is an intriguing example of a state-dependent network, where chromosomal geometry directly relates to genomic activity, which in turn strongly correlates with geometry. Here we examine various aspects of a genomic state-dependent dynamic network. In particular, we elaborate on one of the important ramifications of viewing genomic networks as being state-dependent, namely, their controllability during processes of genomic reorganization such as in cell differentiation.
- Published
- 2011
- Full Text
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38. A functional element necessary for fetal hemoglobin silencing.
- Author
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Sankaran VG, Xu J, Byron R, Greisman HA, Fisher C, Weatherall DJ, Sabath DE, Groudine M, Orkin SH, Premawardhena A, and Bender MA
- Subjects
- Adult, Child, Chromatin Assembly and Disassembly, Female, Gene Deletion, Gene Silencing, Humans, Male, Pedigree, Phenotype, Trans-Activators, Fetal Hemoglobin genetics, Gene Expression Regulation, beta-Globins genetics, beta-Thalassemia genetics
- Abstract
Background: An improved understanding of the regulation of the fetal hemoglobin genes holds promise for the development of targeted therapeutic approaches for fetal hemoglobin induction in the β-hemoglobinopathies. Although recent studies have uncovered trans-acting factors necessary for this regulation, limited insight has been gained into the cis-regulatory elements involved., Methods: We identified three families with unusual patterns of hemoglobin expression, suggestive of deletions in the locus of the β-globin gene (β-globin locus). We performed array comparative genomic hybridization to map these deletions and confirmed breakpoints by means of polymerase-chain-reaction assays and DNA sequencing. We compared these deletions, along with previously mapped deletions, and studied the trans-acting factors binding to these sites in the β-globin locus by using chromatin immunoprecipitation., Results: We found a new (δβ)(0)-thalassemia deletion and a rare hereditary persistence of fetal hemoglobin deletion with identical downstream breakpoints. Comparison of the two deletions resulted in the identification of a small intergenic region required for γ-globin (fetal hemoglobin) gene silencing. We mapped a Kurdish β(0)-thalassemia deletion, which retains the required intergenic region, deletes other surrounding sequences, and maintains fetal hemoglobin silencing. By comparing these deletions and other previously mapped deletions, we elucidated a 3.5-kb intergenic region near the 5' end of the δ-globin gene that is necessary for γ-globin silencing. We found that a critical fetal hemoglobin silencing factor, BCL11A, and its partners bind within this region in the chromatin of adult erythroid cells., Conclusions: By studying three families with unusual deletions in the β-globin locus, we identified an intergenic region near the δ-globin gene that is necessary for fetal hemoglobin silencing. (Funded by the National Institutes of Health and others.).
- Published
- 2011
- Full Text
- View/download PDF
39. Losing control: cancer's catastrophic transition.
- Author
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Rajapakse I, Scalzo D, and Groudine M
- Subjects
- Cell Transformation, Neoplastic, Chromosomes metabolism, DNA chemistry, DNA metabolism, Genomic Instability, Humans, Neoplasms metabolism, Neoplasms pathology, Neoplasms genetics
- Abstract
Adaptability and "emergent" properties are the dominant characteristics of complex systems, whether naturally occurring or engineered. Structurally, a complex system might be made up of a large number of simpler components, or it might be formed from hierarchies of smaller numbers of interacting subsystems and work together to produce a defined function. The nucleus of a cell has all of these features, many of which may become disrupted in cancer and other disease states. The general view is that cancer progresses gradually over time; cells become premalignant, then increasingly abnormal before they become cancerous. However, recent work by Stephens et al. (2011) has revealed that cancer can emerge much more rapidly. Based on DNA sequences from multiple cancer samples of various types, they show that cancer can arise suddenly from a single catastrophic event that causes massive genomic rearrangement.
- Published
- 2011
- Full Text
- View/download PDF
40. On emerging nuclear order.
- Author
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Rajapakse I and Groudine M
- Subjects
- Animals, Chromatin Assembly and Disassembly, Chromosomes physiology, Chromosomes ultrastructure, Gene Regulatory Networks, Humans, Interphase, Models, Genetic, Neoplasms genetics, Translocation, Genetic, Cell Nucleus ultrastructure, Gene Expression Regulation, Intranuclear Space ultrastructure
- Abstract
Although the nonrandom nature of interphase chromosome arrangement is widely accepted, how nuclear organization relates to genomic function remains unclear. Nuclear subcompartments may play a role by offering rich microenvironments that regulate chromatin state and ensure optimal transcriptional efficiency. Technological advances now provide genome-wide and four-dimensional analyses, permitting global characterizations of nuclear order. These approaches will help uncover how seemingly separate nuclear processes may be coupled and aid in the effort to understand the role of nuclear organization in development and disease.
- Published
- 2011
- Full Text
- View/download PDF
41. Functional and mechanistic diversity of distal transcription enhancers.
- Author
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Bulger M and Groudine M
- Subjects
- Animals, Chromatin metabolism, Humans, Promoter Regions, Genetic, Transcription Factors metabolism, Enhancer Elements, Genetic, Gene Expression Regulation, Transcription, Genetic
- Abstract
Biological differences among metazoans and between cell types in a given organism arise in large part due to differences in gene expression patterns. Gene-distal enhancers are key contributors to these expression patterns, exhibiting both sequence diversity and cell type specificity. Studies of long-range interactions indicate that enhancers are often important determinants of nuclear organization, contributing to a general model for enhancer function that involves direct enhancer-promoter contact. However, mechanisms for enhancer function are emerging that do not fit solely within such a model, suggesting that enhancers as a class of DNA regulatory element may be functionally and mechanistically diverse., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
42. Multiple functions of Ldb1 required for beta-globin activation during erythroid differentiation.
- Author
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Song SH, Kim A, Ragoczy T, Bender MA, Groudine M, and Dean A
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Basic Helix-Loop-Helix Transcription Factors chemistry, Basic Helix-Loop-Helix Transcription Factors metabolism, Cell Differentiation genetics, Cell Differentiation physiology, Cell Line, DNA-Binding Proteins antagonists & inhibitors, DNA-Binding Proteins chemistry, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, Embryonic Stem Cells cytology, Embryonic Stem Cells metabolism, Erythroid Precursor Cells cytology, Erythroid Precursor Cells metabolism, Erythropoiesis genetics, GATA1 Transcription Factor chemistry, GATA1 Transcription Factor metabolism, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, LIM Domain Proteins, Locus Control Region, Metalloproteins chemistry, Metalloproteins metabolism, Mice, Mice, Knockout, Models, Biological, Multiprotein Complexes, Phosphorylation, Positive Transcriptional Elongation Factor B metabolism, Promoter Regions, Genetic, Protein Stability, Proto-Oncogene Proteins chemistry, Proto-Oncogene Proteins metabolism, RNA Polymerase II chemistry, RNA Polymerase II metabolism, Serine chemistry, T-Cell Acute Lymphocytic Leukemia Protein 1, beta-Globins deficiency, beta-Globins genetics, DNA-Binding Proteins metabolism, Erythropoiesis physiology, beta-Globins metabolism
- Abstract
Ldb1 and erythroid partners SCL, GATA-1, and LMO2 form a complex that is required to establish spatial proximity between the β-globin locus control region and gene and for transcription activation during erythroid differentiation. Here we show that Ldb1 controls gene expression at multiple levels. Ldb1 stabilizes its erythroid complex partners on β-globin chromatin, even though it is not one of the DNA-binding components. In addition, Ldb1 is necessary for enrichment of key transcriptional components in the locus, including P-TEFb, which phosphorylates Ser2 of the RNA polymerase C-terminal domain for efficient elongation. Furthermore, reduction of Ldb1 results in the inability of the locus to migrate away from the nuclear periphery, which is necessary to achieve robust transcription of β-globin in nuclear transcription factories. Ldb1 contributes these critical functions at both embryonic and adult stages of globin gene expression. These results implicate Ldb1 as a factor that facilitates nuclear relocation for transcription activation.
- Published
- 2010
- Full Text
- View/download PDF
43. Networking the nucleus.
- Author
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Rajapakse I, Scalzo D, Tapscott SJ, Kosak ST, and Groudine M
- Subjects
- Animals, Gene Expression Regulation, Humans, Models, Theoretical, Cell Differentiation genetics, Cell Nucleus physiology, Chromosomes, Gene Regulatory Networks, Signal Transduction genetics, Systems Biology
- Abstract
The nuclei of differentiating cells exhibit several fundamental principles of self-organization. They are composed of many dynamical units connected physically and functionally to each other--a complex network--and the different parts of the system are mutually adapted and produce a characteristic end state. A unique cell-specific signature emerges over time from complex interactions among constituent elements that delineate coordinate gene expression and chromosome topology. Each element itself consists of many interacting components, all dynamical in nature. Self-organizing systems can be simplified while retaining complex information using approaches that examine the relationship between elements, such as spatial relationships and transcriptional information. These relationships can be represented using well-defined networks. We hypothesize that during the process of differentiation, networks within the cell nucleus rewire according to simple rules, from which a higher level of order emerges. Studying the interaction within and among networks provides a useful framework for investigating the complex organization and dynamic function of the nucleus.
- Published
- 2010
- Full Text
- View/download PDF
44. Enhancers: the abundance and function of regulatory sequences beyond promoters.
- Author
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Bulger M and Groudine M
- Subjects
- Animals, Cell Nucleus metabolism, Chromatin metabolism, DNA chemistry, DNA metabolism, Drosophila genetics, Humans, Models, Biological, Nuclear Proteins genetics, Nuclear Proteins metabolism, Promoter Regions, Genetic, Enhancer Elements, Genetic, Gene Expression Regulation, Developmental
- Abstract
Transcriptional control in mammals and Drosophila is often mediated by regulatory sequences located far from gene promoters. Different classes of such elements - particularly enhancers, but also locus control regions and insulators - have been defined by specific functional assays, although it is not always clear how these assays relate to the function of these elements within their native loci. Recent advances in genomics suggest, however, that such elements are highly abundant within the genome and may represent the primary mechanism by which cell- and developmental-specific gene expression is accomplished. In this review, we discuss the functional parameters of enhancers as defined by specific assays, along with the frequency with which they occur in the genome. In addition, we examine the available evidence for the mechanism by which such elements communicate or interact with the promoters they regulate., (Copyright 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
45. Getting connected in the globin interactome.
- Author
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Ragoczy T and Groudine M
- Subjects
- Animals, Erythroid Cells cytology, Genome-Wide Association Study, Globins metabolism, Kruppel-Like Transcription Factors genetics, Kruppel-Like Transcription Factors metabolism, Mice, Models, Biological, Oligonucleotide Array Sequence Analysis, Erythroid Cells metabolism, Gene Expression Profiling, Gene Regulatory Networks genetics, Globins genetics
- Abstract
A new study provides compelling evidence that transcriptional regulation and three-dimensional genomic architecture are linked. The alpha- and beta-globin loci associate with hundreds of active genes across the genome at transcription factories in erythroid cells, and specialized Klf1-containing transcription factories mediate the association of Klf1-regulated genes.
- Published
- 2010
- Full Text
- View/download PDF
46. Histone hyperacetylation within the beta-globin locus is context-dependent and precedes high-level gene expression.
- Author
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Fromm G, de Vries C, Byron R, Fields J, Fiering S, Groudine M, Bender MA, Palis J, and Bulger M
- Subjects
- Acetylation, Animals, Mice, Protein Structure, Tertiary physiology, Embryo, Mammalian embryology, Gene Expression Regulation, Developmental physiology, Histones metabolism, Promoter Regions, Genetic physiology, Quantitative Trait Loci physiology, beta-Globins biosynthesis
- Abstract
Active gene promoters are associated with covalent histone modifications, such as hyperacetylation, which can modulate chromatin structure and stabilize binding of transcription factors that recognize these modifications. At the beta-globin locus and several other loci, however, histone hyperacetylation extends beyond the promoter, over tens of kilobases; we term such patterns of histone modifications "hyperacetylated domains." Little is known of either the mechanism by which these domains form or their function. Here, we show that domain formation within the murine beta-globin locus occurs before either high-level gene expression or erythroid commitment. Analysis of beta-globin alleles harboring deletions of promoters or the locus control region demonstrates that these sequences are not required for domain formation, suggesting the existence of additional regulatory sequences within the locus. Deletion of embryonic globin gene promoters, however, resulted in the formation of a hyperacetylated domain over these genes in definitive erythroid cells, where they are otherwise inactive. Finally, sequences within beta-globin domains exhibit hyperacetylation in a context-dependent manner, and domains are maintained when transcriptional elongation is inhibited. These data narrow the range of possible mechanisms by which hyperacetylated domains form.
- Published
- 2009
- Full Text
- View/download PDF
47. Comprehensive mapping of long-range interactions reveals folding principles of the human genome.
- Author
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Lieberman-Aiden E, van Berkum NL, Williams L, Imakaev M, Ragoczy T, Telling A, Amit I, Lajoie BR, Sabo PJ, Dorschner MO, Sandstrom R, Bernstein B, Bender MA, Groudine M, Gnirke A, Stamatoyannopoulos J, Mirny LA, Lander ES, and Dekker J
- Subjects
- Biotin, Cell Line, Transformed, Chromatin Immunoprecipitation, Computational Biology, Gene Library, Humans, In Situ Hybridization, Fluorescence, Models, Molecular, Monte Carlo Method, Nucleic Acid Conformation, Principal Component Analysis, Protein Conformation, Sequence Analysis, DNA, Cell Nucleus ultrastructure, Chromatin chemistry, Chromosomes, Human chemistry, Chromosomes, Human ultrastructure, DNA chemistry, Genome, Human
- Abstract
We describe Hi-C, a method that probes the three-dimensional architecture of whole genomes by coupling proximity-based ligation with massively parallel sequencing. We constructed spatial proximity maps of the human genome with Hi-C at a resolution of 1 megabase. These maps confirm the presence of chromosome territories and the spatial proximity of small, gene-rich chromosomes. We identified an additional level of genome organization that is characterized by the spatial segregation of open and closed chromatin to form two genome-wide compartments. At the megabase scale, the chromatin conformation is consistent with a fractal globule, a knot-free, polymer conformation that enables maximally dense packing while preserving the ability to easily fold and unfold any genomic locus. The fractal globule is distinct from the more commonly used globular equilibrium model. Our results demonstrate the power of Hi-C to map the dynamic conformations of whole genomes.
- Published
- 2009
- Full Text
- View/download PDF
48. Developmental and species-divergent globin switching are driven by BCL11A.
- Author
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Sankaran VG, Xu J, Ragoczy T, Ippolito GC, Walkley CR, Maika SD, Fujiwara Y, Ito M, Groudine M, Bender MA, Tucker PW, and Orkin SH
- Subjects
- Animals, Carrier Proteins genetics, DNA-Binding Proteins, Embryo, Mammalian metabolism, Evolution, Molecular, Fetus metabolism, Gene Silencing, Hematopoiesis, Humans, Mice, Nuclear Proteins genetics, Repressor Proteins, Species Specificity, beta-Globins genetics, gamma-Globins genetics, Carrier Proteins metabolism, Gene Expression Regulation, Developmental, Globins genetics, Nuclear Proteins metabolism
- Abstract
The contribution of changes in cis-regulatory elements or trans-acting factors to interspecies differences in gene expression is not well understood. The mammalian beta-globin loci have served as a model for gene regulation during development. Transgenic mice containing the human beta-globin locus, consisting of the linked embryonic (epsilon), fetal (gamma) and adult (beta) genes, have been used as a system to investigate the temporal switch from fetal to adult haemoglobin, as occurs in humans. Here we show that the human gamma-globin (HBG) genes in these mice behave as murine embryonic globin genes, revealing a limitation of the model and demonstrating that critical differences in the trans-acting milieu have arisen during mammalian evolution. We show that the expression of BCL11A, a repressor of human gamma-globin expression identified by genome-wide association studies, differs between mouse and human. Developmental silencing of the mouse embryonic globin and human gamma-globin genes fails to occur in mice in the absence of BCL11A. Thus, BCL11A is a critical mediator of species-divergent globin switching. By comparing the ontogeny of beta-globin gene regulation in mice and humans, we have shown that alterations in the expression of a trans-acting factor constitute a critical driver of gene expression changes during evolution.
- Published
- 2009
- Full Text
- View/download PDF
49. The emergence of lineage-specific chromosomal topologies from coordinate gene regulation.
- Author
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Rajapakse I, Perlman MD, Scalzo D, Kooperberg C, Groudine M, and Kosak ST
- Subjects
- Cell Differentiation genetics, Cell Lineage genetics, Chromosomes genetics, Gene Expression Regulation
- Abstract
Although the importance of chromosome organization during mitosis is clear, it remains to be determined whether the nucleus assumes other functionally relevant chromosomal topologies. We have previously shown that homologous chromosomes have a tendency to associate during hematopoiesis according to their distribution of coregulated genes, suggesting cell-specific nuclear organization. Here, using the mathematical approaches of distance matrices and coupled oscillators, we model the dynamic relationship between gene expression and chromosomal associations during the differentiation of a multipotential hematopoietic progenitor. Our analysis reveals dramatic changes in total genomic order: Commitment of the progenitor results in an initial increase in entropy at both the level of gene coregulation and chromosomal organization, which we suggest represents a phase transition, followed by a progressive decline in entropy during differentiation. The stabilization of a highly ordered state in the differentiated cell types results in lineage-specific chromosomal topologies and is related to the emergence of coherence-or self-organization-between chromosomal associations and coordinate gene regulation. We discuss how these observations may be generally relevant to cell fate decisions encountered by progenitor/stem cells.
- Published
- 2009
- Full Text
- View/download PDF
50. The nucleus inside out--through a rod darkly.
- Author
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Ragoczy T and Groudine M
- Subjects
- Animals, Euchromatin chemistry, Heterochromatin chemistry, Mice, Vision, Ocular, Cell Nucleus genetics, Retinal Rod Photoreceptor Cells cytology, Retinal Rod Photoreceptor Cells physiology
- Abstract
In the nuclei of eukaryotic cells, euchromatin is located at the center, whereas heterochromatin is found at the periphery and is interspersed in the nucleoplasm. Solovei et al. (2009) now reveal that this normal pattern is reversed in the retinal rod cells of mice. This inversion might serve to maximize light transmission to photoreceptors in nocturnal mammals.
- Published
- 2009
- Full Text
- View/download PDF
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