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1. Comparative analysis of the transcriptome across distant species

Author

Gerstein, MB, Rozowsky, J, Yan, KK, Wang, D, Cheng, C, Brown, JB, Davis, CA, Hillier, L, Sisu, C, Li, JJ, Pei, B, Harmanci, AO, Duff, MO, Djebali, S, Alexander, RP, Alver, BH, Auerbach, R, Bell, K, Bickel, PJ, Boeck, ME, Boley, NP, Booth, BW, Cherbas, L, Cherbas, P, Di, C, Dobin, A, Drenkow, J, Ewing, B, Fang, G, Fastuca, M, Feingold, EA, Frankish, A, Gao, G, Good, PJ, Guigó, R, Hammonds, A, Harrow, J, Hoskins, RA, Howald, C, Hu, L, Huang, H, Hubbard, TJP, Huynh, C, Jha, S, Kasper, D, Kato, M, Kaufman, TC, Kitchen, RR, Ladewig, E, Lagarde, J, Lai, E, Leng, J, Lu, Z, MacCoss, M, May, G, McWhirter, R, Merrihew, G, Miller, DM, Mortazavi, A, Murad, R, Oliver, B, Olson, S, Park, PJ, Pazin, MJ, Perrimon, N, Pervouchine, D, Reinke, V, Reymond, A, and Robinson, G

Subjects
animal structures, fungi
Abstract

The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features. Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a â universal model' based on a single set of organism-independent parameters. © 2014 Macmillan Publishers Limited.

Published
2014

2. Comparative analysis of metazoan chromatin organization

Author

Ho, JWK, Jung, YL, Liu, T, Alver, BH, Lee, S, Ikegami, K, Sohn, KA, Minoda, A, Tolstorukov, MY, Appert, A, Parker, SCJ, Gu, T, Kundaje, A, Riddle, NC, Bishop, E, Egelhofer, TA, Hu, SS, Alekseyenko, AA, Rechtsteiner, A, Asker, D, Belsky, JA, Bowman, SK, Chen, QB, Chen, RAJ, Day, DS, Dong, Y, Dose, AC, Duan, X, Epstein, CB, Ercan, S, Feingold, EA, Ferrari, F, Garrigues, JM, Gehlenborg, N, Good, PJ, Haseley, P, He, D, Herrmann, M, Hoffman, MM, Jeffers, TE, Kharchenko, PV, Kolasinska-Zwierz, P, Kotwaliwale, CV, Kumar, N, Langley, SA, Larschan, EN, Latorre, I, Libbrecht, MW, Lin, X, Park, R, Pazin, MJ, Pham, HN, Plachetka, A, Qin, B, Schwartz, YB, Shoresh, N, Stempor, P, Vielle, A, Wang, C, Whittle, CM, Xue, H, Kingston, RE, Kim, JH, and Bernstein, BE

Abstract

Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths. To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function. © 2014 Macmillan Publishers Limited.

Published
2014

3. An integrated encyclopedia of DNA elements in the human genome

Author

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, Ernst, J, Furey, TS, Gerstein, M, Giardine, B, Greven, M, Hardison, RC, Harris, RS, Herrero, J, Hoffman, MM, Iyer, S, Kellis, M, Kheradpour, P, Lassmann, T, Li, Q, Lin, X, Marinov, GK, Merkel, A, Mortazavi, A, Parker, SCJ, Reddy, TE, Rozowsky, J, Schlesinger, F, Thurman, RE, Wang, J, Ward, LD, Whitfield, TW, Wilder, SP, Wu, W, Xi, HS, Yip, KY, Zhuang, J, Bernstein, BE, Green, ED, Gunter, C, Snyder, M, Pazin, MJ, Lowdon, RF, Dillon, LAL, Adams, LB, Kelly, CJ, Zhang, J, Wexler, JR, Good, PJ, Feingold, EA, Crawford, GE, Dekker, J, Elnitski, L, Farnham, PJ, Giddings, MC, Gingeras, TR, Guigó, R, Hubbard, TJ, Kent, WJ, Lieb, JD, Margulies, EH, and Myers, RM

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. © 2012 Macmillan Publishers Limited. All rights reserved.

Published
2012

4. The breakpoint of a large deletion causing hereditary persistence of fetal hemoglobin occurs within an erythroid DNA domain remote from the beta-globin gene cluster

Author

Feingold, EA and Forget, BG

Abstract

The DNA juxtaposed to the gamma-globin genes as a result of a large deletion associated with hereditary persistence of fetal hemoglobin (HPFH) was studied to define the role it may play in maintaining active expression of these genes in adult erythroid cells. The DNA located immediately 3' to the deletion breakpoint was found to function as an enhancer element in gene transfer experiments and to be specifically hypomethylated in normal erythroid cells of both fetal and adult origin. This DNA also contains a long open reading frame encoding a polypeptide chain 292 amino acids in length. Therefore, in this form of HPFH (HPFH-1), the continued expression of gamma-globin genes in adult life may result from the inclusion of these genes within a new chromosomal domain that is potentially transcriptionally active in adult erythroid cells. The 3' breakpoint of another large deletion causing delta beta thalassemia rather than HPFH was also identified. This deletion (Spanish G gamma A gamma (delta beta) degrees thalassemia) is nearly identical in size and location to that of HPFH- 1, but extends an additional 8.5 to 9 kb in the 3'direction, and therefore results in loss of the sequences near the 3' breakpoint of HPFH-1. Thus, the presence of these sequences appears to be important for the expression of the HPFH phenotype.

Published
1989
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5. An integrated encyclopedia of DNA elements in the human genome

Author

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

Subjects
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

6. A User's Guide to the Encyclopedia of DNA Elements (ENCODE)

Author

Zhi Lu, Giltae Song, Troy W. Whitfield, Vishwanath R. Iyer, Teresa Vales, Angelika Merkel, Max Libbrecht, David Haussler, Ting Wang, Kristen Lee, Lingyun Song, Richard M. Myers, Alfonso Valencia, Rachel A. Harte, Xiaoqin Xu, Lucas D. Ward, Hazuki Takahashi, Nathan C. Sheffield, Thomas Derrien, Georgi K. Marinov, Eric D. Nguyen, Bernard B. Suh, Brian J. Raney, Richard Sandstrom, Thomas D. Tullius, Benoit Miotto, Alexander Dobin, Youhan Xu, Lukas Habegger, Ian Dunham, Brian A. Risk, Paul G. Giresi, Morgan C. Giddings, Hualin Xi, Anshul Kundaje, Robert S. Harris, Devin Absher, Peter J. Bickel, Yanbao Yu, Browen Aken, Colin Kingswood, Bryan R. Lajoie, Peter J. Good, Katrina Learned, Laura Elnitski, Shirley Pepke, Brandon King, Piero Carninci, Xinqiong Yang, Ghia Euskirchen, Kathryn Beal, Christelle Borel, Michael Muratet, Robert L. Grossman, David G. Knowles, Zarmik Moqtaderi, Veronika Boychenko, Steven P. Wilder, Michael L. Tress, Florencia Pauli, Alan P. Boyle, Andrea Tanzer, Philipp Kapranov, Serafim Batzoglou, Audra K. Johnson, Jun Neri, Nitin Bhardwaj, Elise A. Feingold, Venkat S. Malladi, Michael M. Hoffman, William Stafford Noble, Andrea Sboner, Mark Gerstein, Stephanie L. Parker, Jacqueline Dumais, Felix Schlesinger, Deborah R. Winter, Randall H. Brown, Thanh Truong, Rebecca F. Lowdon, Paolo Ribeca, Brooke Rhead, Peggy J. Farnham, Krista Thibeault, Terrence S. Furey, Donna Karolchik, Alec Victorsen, Xiaoan Ruan, Rehab F. Abdelhamid, Amy S. Nesmith, Jing Wang, Nicholas M. Luscombe, Alina R. Cao, Diane Trout, Teri Slifer, Peter E. Newburger, Cricket A. Sloan, Dimitra Lotakis, Stephen M. J. Searle, Ali Mortazavi, Alexandra Bignell, Alex Reynolds, Orion J. Buske, Chris Zaleski, Theresa K. Canfield, Ian Bell, Jin Lian, Vanessa K. Swing, Katalin Toth Fejes, Catherine Ucla, Robert E. Thurman, Jacqueline Chrast, Wei Lin, Tim Hubbard, Gary Saunders, Minyi Shi, Vihra Sotirova, Sherman M. Weissman, Jason D. Lieb, Richard Humbert, Kevin M. Bowling, Assaf Gordon, Tarjei S. Mikkelsen, Jing Leng, Thomas R. Gingeras, Fabian Grubert, Nader Jameel, Jost Vielmetter, Hannah Monahan, Preti Jain, Lindsay L. Waite, Tony Shafer, Joel Rozowsky, Michael Coyne, Brian Reed, M. Kay, Harsha P. Gunawardena, Ross C. Hardison, Gavin Sherlock, Alexandra Charos, Joseph D. Fleming, Ann S. Zweig, Jason Gertz, Rajinder Kaul, Xianjun Dong, Alexandre Reymond, Carrie A. Davis, Haiyan Huang, Chao Cheng, Marco Mariotti, Phil Lacroute, Jason A. Dilocker, Kenneth McCue, R. Robilotto, Stylianos E. Antonarakis, Sridar V. Chittur, Justin Jee, Barbara J. Wold, Sudipto K. Chakrabortty, Erica Dumais, Amartya Sanyal, Nathan Boley, Tianyuan Wang, Julien Lagarde, Anthony Kirilusha, Jonathan B. Preall, Kevin Roberts, Erika Giste, Hugo Y. K. Lam, Alvis Brazma, Gregory J. Hannon, Eric Rynes, Philippe Batut, Kevin Struhl, Margus Lukk, Manching Ku, Suganthi Balasubramanian, Sonali Jha, Jorg Drenkow, W. James Kent, Michael Snyder, Jie Wang, Anna Battenhouse, Charles B. Epstein, Rami Rauch, Christopher Shestak, John A. Stamatoyannopoulos, Gaurab Mukherjee, Cédric Howald, Tanya Kutyavin, Huaien Wang, Scott A. Tenenbaum, Wan Ting Poh, Kate R. Rosenbloom, Manolis Kellis, Pauline A. Fujita, Linfeng Wu, Anita Bansal, Molly Weaver, Linda L. Grasfeder, Peter J. Sabo, Qiang Li, Melissa S. Cline, Robert M. Kuhn, Darin London, Seth Frietze, Atif Shahab, Shane Neph, Damian Keefe, James B. Brown, Mark Diekhans, Webb Miller, Katherine Aylor Fisher, Jiang Du, Hadar H. Sheffer, Sarah Djebali, Frank Doyle, Nathan Lamarre-Vincent, Chia-Lin Wei, Laura A.L. Dillon, Jennifer Harrow, Robert C. Altshuler, Tyler Alioto, Raymond K. Auerbach, Adam Frankish, Rebekka O. Sprouse, Patrick J. Collins, E. Christopher Partridge, Zheng Liu, Yoichiro Shibata, Elliott H. Margulies, Abigail K. Ebersol, Kimberly A. Showers, Eric D. Green, Krishna M. Roskin, Job Dekker, Barbara N. Pusey, Ekta Khurana, Gilberto DeSalvo, Yijun Ruan, Hao Wang, Jainab Khatun, Henriette O'Geen, Alexej Abyzov, Brian Williams, Ryan M. McDaniell, Maya Kasowski, Manoj Hariharan, Felix Kokocinski, Gloria Despacio-Reyes, Zhancheng Zhang, Subhradip Karmakar, Ewan Birney, Koon-Kiu Yan, Xian Chen, Shinny Vong, Daniel Sobral, Nick Bild, Seul K.C. Kim, Timo Lassmann, Li Wang, Minerva E. Sanchez, Vaughan Roach, Theodore Gibson, Stephen C. J. Parker, Michael F. Lin, Patrick A. Navas, Laurence R. Meyer, Luiz O. F. Penalva, Bradley E. Bernstein, Kevin P. White, Emilie Aït Yahya Graison, Juan M. Vaquerizas, Sushma Iyengar, Kimberly M. Newberry, Akshay Bhinge, Xiaolan Zhang, Kim Bell, Yoshihide Hayashizaki, Lucas Lochovsky, Noam Shoresh, Hagen Tilgner, Philip Cayting, Dorrelyn Patacsil, Timothy E. Reddy, Eric Haugen, Katherine E. Varley, M. van Baren, Nathan D. Trinklein, Bum Kyu Lee, Tristan Frum, Marianne Lindahl-Allen, Timothy Durham, Roderic Guigó, Christopher W. Maier, Micha Sammeth, Debasish Raha, Timothy R. Dreszer, Benedict Paten, Robbyn Issner, Michael R. Brent, Kevin Y. Yip, Kim Blahnik, Jason Ernst, Zhiping Weng, Henry Amrhein, Arend Sidow, Javier Herrero, Hui Gao, Stephen G. Landt, Pouya Kheradpour, Galt P. Barber, Gregory E. Crawford, Toby Hunt, HudsonAlpha Institute for Biotechnology [Huntsville, AL], ENCODE Project Consortium : Myers RM, Stamatoyannopoulos J, Snyder M, Dunham I, Hardison RC, Bernstein BE, Gingeras TR, Kent WJ, Birney E, Wold B, Crawford GE, Bernstein BE, Epstein CB, Shoresh N, Ernst J, Mikkelsen TS, Kheradpour P, Zhang X, Wang L, Issner R, Coyne MJ, Durham T, Ku M, Truong T, Ward LD, Altshuler RC, Lin MF, Kellis M, Gingeras TR, Davis CA, Kapranov P, Dobin A, Zaleski C, Schlesinger F, Batut P, Chakrabortty S, Jha S, Lin W, Drenkow J, Wang H, Bell K, Gao H, Bell I, Dumais E, Dumais J, Antonarakis SE, Ucla C, Borel C, Guigo R, Djebali S, Lagarde J, Kingswood C, Ribeca P, Sammeth M, Alioto T, Merkel A, Tilgner H, Carninci P, Hayashizaki Y, Lassmann T, Takahashi H, Abdelhamid RF, Hannon G, Fejes-Toth K, Preall J, Gordon A, Sotirova V, Reymond A, Howald C, Graison E, Chrast J, Ruan Y, Ruan X, Shahab A, Ting Poh W, Wei CL, Crawford GE, Furey TS, Boyle AP, Sheffield NC, Song L, Shibata Y, Vales T, Winter D, Zhang Z, London D, Wang T, Birney E, Keefe D, Iyer VR, Lee BK, McDaniell RM, Liu Z, Battenhouse A, Bhinge AA, Lieb JD, Grasfeder LL, Showers KA, Giresi PG, Kim SK, Shestak C, Myers RM, Pauli F, Reddy TE, Gertz J, Partridge EC, Jain P, Sprouse RO, Bansal A, Pusey B, Muratet MA, Varley KE, Bowling KM, Newberry KM, Nesmith AS, Dilocker JA, Parker SL, Waite LL, Thibeault K, Roberts K, Absher DM, Wold B, Mortazavi A, Williams B, Marinov G, Trout D, Pepke S, King B, McCue K, Kirilusha A, DeSalvo G, Fisher-Aylor K, Amrhein H, Vielmetter J, Sherlock G, Sidow A, Batzoglou S, Rauch R, Kundaje A, Libbrecht M, Margulies EH, Parker SC, Elnitski L, Green ED, Hubbard T, Harrow J, Searle S, Kokocinski F, Aken B, Frankish A, Hunt T, Despacio-Reyes G, Kay M, Mukherjee G, Bignell A, Saunders G, Boychenko V, Van Baren M, Brown RH, Khurana E, Balasubramanian S, Zhang Z, Lam H, Cayting P, Robilotto R, Lu Z, Guigo R, Derrien T, Tanzer A, Knowles DG, Mariotti M, James Kent W, Haussler D, Harte R, Diekhans M, Kellis M, Lin M, Kheradpour P, Ernst J, Reymond A, Howald C, Graison EA, Chrast J, Tress M, Rodriguez JM, Snyder M, Landt SG, Raha D, Shi M, Euskirchen G, Grubert F, Kasowski M, Lian J, Cayting P, Lacroute P, Xu Y, Monahan H, Patacsil D, Slifer T, Yang X, Charos A, Reed B, Wu L, Auerbach RK, Habegger L, Hariharan M, Rozowsky J, Abyzov A, Weissman SM, Gerstein M, Struhl K, Lamarre-Vincent N, Lindahl-Allen M, Miotto B, Moqtaderi Z, Fleming JD, Newburger P, Farnham PJ, Frietze S, O'Geen H, Xu X, Blahnik KR, Cao AR, Iyengar S, Stamatoyannopoulos JA, Kaul R, Thurman RE, Wang H, Navas PA, Sandstrom R, Sabo PJ, Weaver M, Canfield T, Lee K, Neph S, Roach V, Reynolds A, Johnson A, Rynes E, Giste E, Vong S, Neri J, Frum T, Johnson EM, Nguyen ED, Ebersol AK, Sanchez ME, Sheffer HH, Lotakis D, Haugen E, Humbert R, Kutyavin T, Shafer T, Dekker J, Lajoie BR, Sanyal A, James Kent W, Rosenbloom KR, Dreszer TR, Raney BJ, Barber GP, Meyer LR, Sloan CA, Malladi VS, Cline MS, Learned K, Swing VK, Zweig AS, Rhead B, Fujita PA, Roskin K, Karolchik D, Kuhn RM, Haussler D, Birney E, Dunham I, Wilder SP, Keefe D, Sobral D, Herrero J, Beal K, Lukk M, Brazma A, Vaquerizas JM, Luscombe NM, Bickel PJ, Boley N, Brown JB, Li Q, Huang H, Gerstein M, Habegger L, Sboner A, Rozowsky J, Auerbach RK, Yip KY, Cheng C, Yan KK, Bhardwaj N, Wang J, Lochovsky L, Jee J, Gibson T, Leng J, Du J, Hardison RC, Harris RS, Song G, Miller W, Haussler D, Roskin K, Suh B, Wang T, Paten B, Noble WS, Hoffman MM, Buske OJ, Weng Z, Dong X, Wang J, Xi H, Tenenbaum SA, Doyle F, Penalva LO, Chittur S, Tullius TD, Parker SC, White KP, Karmakar S, Victorsen A, Jameel N, Bild N, Grossman RL, Snyder M, Landt SG, Yang X, Patacsil D, Slifer T, Dekker J, Lajoie BR, Sanyal A, Weng Z, Whitfield TW, Wang J, Collins PJ, Trinklein ND, Partridge EC, Myers RM, Giddings MC, Chen X, Khatun J, Maier C, Yu Y, Gunawardena H, Risk B, Feingold EA, Lowdon RF, Dillon LA, Good PJ, Harrow J, Searle S., Becker, Peter B, Broad Institute of MIT and Harvard, Lincoln Laboratory, Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology. Department of Physics, Kellis, Manolis, Epstein, Charles B., Bernstein, Bradley E., Shoresh, Noam, Ernst, Jason, Mikkelsen, Tarjei Sigurd, Kheradpour, Pouya, Zhang, Xiaolan, Wang, Li, Issner, Robbyn, Coyne, Michael J., Durham, Timothy, Ku, Manching, Truong, Thanh, Ward, Lucas D., Altshuler, Robert Charles, Lin, Michael F., ENCODE Project Consortium, Antonarakis, Stylianos, and Miotto, Benoit

Subjects
RNA, Messenger/genetics, [SDV]Life Sciences [q-bio], Messenger, Genoma humà, Genome, Medical and Health Sciences, 0302 clinical medicine, Models, ddc:576.5, Biology (General), Conserved Sequence, Genetics, 0303 health sciences, General Neuroscience, RNA-Binding Proteins, Genomics, Biological Sciences, Chromatin, 3. Good health, [SDV] Life Sciences [q-bio], DNA-Binding Proteins, Gene Components, 030220 oncology & carcinogenesis, DNA methylation, Encyclopedia, HIV/AIDS, Proteïnes de la sang -- Aspectes genètics, General Agricultural and Biological Sciences, Databases, Nucleic Acid, Human, Research Article, Quality Control, Process (engineering), QH301-705.5, 1.1 Normal biological development and functioning, Computational biology, Biology, ENCODE, General Biochemistry, Genetics and Molecular Biology, Chromatin/metabolism, Vaccine Related, 03 medical and health sciences, Databases, Genetic, Underpinning research, Humans, RNA, Messenger, RNA-Binding Proteins/genetics/metabolism, Vaccine Related (AIDS), Gene, 030304 developmental biology, Internet, General Immunology and Microbiology, Nucleic Acid, Agricultural and Veterinary Sciences, Base Sequence, Models, Genetic, Genome, Human, Prevention, Human Genome, Computational Biology, DNA Methylation, ENCODE Project Consortium, Gene Expression Regulation, DNA-Binding Proteins/genetics/metabolism, RNA, Human genome, Immunization, Generic health relevance, Developmental Biology
Abstract

The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome., National Human Genome Research Institute (U.S.), National Institutes of Health (U.S.)

Published
2011

7. Author Correction: Perspectives on ENCODE.

Author

Snyder MP, Gingeras TR, Moore JE, Weng Z, Gerstein MB, Ren B, Hardison RC, Stamatoyannopoulos JA, Graveley BR, Feingold EA, Pazin MJ, Pagan M, Gilchrist DA, Hitz BC, Cherry JM, Bernstein BE, Mendenhall EM, Zerbino DR, Frankish A, Flicek P, and Myers RM

Published
2022
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8. Strategic vision for improving human health at The Forefront of Genomics.

Author

Green ED, Gunter C, Biesecker LG, Di Francesco V, Easter CL, Feingold EA, Felsenfeld AL, Kaufman DJ, Ostrander EA, Pavan WJ, Phillippy AM, Wise AL, Dayal JG, Kish BJ, Mandich A, Wellington CR, Wetterstrand KA, Bates SA, Leja D, Vasquez S, Gahl WA, Graham BJ, Kastner DL, Liu P, Rodriguez LL, Solomon BD, Bonham VL, Brody LC, Hutter CM, and Manolio TA

Subjects
Biomedical Research economics, COVID-19 genetics, Genomics economics, Humans, National Human Genome Research Institute (U.S.) economics, Social Change, Translational Research, Biomedical economics, United States, Biomedical Research trends, Genome, Human genetics, Genomics trends, Public Health standards, Translational Research, Biomedical trends
Abstract

Starting with the launch of the Human Genome Project three decades ago, and continuing after its completion in 2003, genomics has progressively come to have a central and catalytic role in basic and translational research. In addition, studies increasingly demonstrate how genomic information can be effectively used in clinical care. In the future, the anticipated advances in technology development, biological insights, and clinical applications (among others) will lead to more widespread integration of genomics into almost all areas of biomedical research, the adoption of genomics into mainstream medical and public-health practices, and an increasing relevance of genomics for everyday life. On behalf of the research community, the National Human Genome Research Institute recently completed a multi-year process of strategic engagement to identify future research priorities and opportunities in human genomics, with an emphasis on health applications. Here we describe the highest-priority elements envisioned for the cutting-edge of human genomics going forward-that is, at 'The Forefront of Genomics'.

Published
2020
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9. Perspectives on ENCODE.

Author

Snyder MP, Gingeras TR, Moore JE, Weng Z, Gerstein MB, Ren B, Hardison RC, Stamatoyannopoulos JA, Graveley BR, Feingold EA, Pazin MJ, Pagan M, Gilchrist DA, Hitz BC, Cherry JM, Bernstein BE, Mendenhall EM, Zerbino DR, Frankish A, Flicek P, and Myers RM

Subjects
Animals, Binding Sites, Chromatin genetics, Chromatin metabolism, DNA Methylation, Gene Expression Regulation genetics, Genome, Human genetics, Histones metabolism, Humans, Mice, Quality Control, Regulatory Sequences, Nucleic Acid genetics, Transcription Factors metabolism, Databases, Genetic standards, Databases, Genetic trends, Genome genetics, Genomics standards, Genomics trends, Molecular Sequence Annotation standards
Abstract

The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression 1 . The project has been extended to model organisms, particularly the mouse. In the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.

Published
2020
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10. A comparative encyclopedia of DNA elements in the mouse genome.

Author

Yue F, Cheng Y, Breschi A, Vierstra J, Wu W, Ryba T, Sandstrom R, Ma Z, Davis C, Pope BD, Shen Y, Pervouchine DD, Djebali S, Thurman RE, Kaul R, Rynes E, Kirilusha A, Marinov GK, Williams BA, Trout D, Amrhein H, Fisher-Aylor K, Antoshechkin I, DeSalvo G, See LH, Fastuca M, Drenkow J, Zaleski C, Dobin A, Prieto P, Lagarde J, Bussotti G, Tanzer A, Denas O, Li K, Bender MA, Zhang M, Byron R, Groudine MT, McCleary D, Pham L, Ye Z, Kuan S, Edsall L, Wu YC, Rasmussen MD, Bansal MS, Kellis M, Keller CA, Morrissey CS, Mishra T, Jain D, Dogan N, Harris RS, Cayting P, Kawli T, Boyle AP, Euskirchen G, Kundaje A, Lin S, Lin Y, Jansen C, Malladi VS, Cline MS, Erickson DT, Kirkup VM, Learned K, Sloan CA, Rosenbloom KR, Lacerda de Sousa B, Beal K, Pignatelli M, Flicek P, Lian J, Kahveci T, Lee D, Kent WJ, Ramalho Santos M, Herrero J, Notredame C, Johnson A, Vong S, Lee K, Bates D, Neri F, Diegel M, Canfield T, Sabo PJ, Wilken MS, Reh TA, Giste E, Shafer A, Kutyavin T, Haugen E, Dunn D, Reynolds AP, Neph S, Humbert R, Hansen RS, De Bruijn M, Selleri L, Rudensky A, Josefowicz S, Samstein R, Eichler EE, Orkin SH, Levasseur D, Papayannopoulou T, Chang KH, Skoultchi A, Gosh S, Disteche C, Treuting P, Wang Y, Weiss MJ, Blobel GA, Cao X, Zhong S, Wang T, Good PJ, Lowdon RF, Adams LB, Zhou XQ, Pazin MJ, Feingold EA, Wold B, Taylor J, Mortazavi A, Weissman SM, Stamatoyannopoulos JA, Snyder MP, Guigo R, Gingeras TR, Gilbert DM, Hardison RC, Beer MA, and Ren B

Subjects
Animals, Cell Lineage genetics, Chromatin genetics, Chromatin metabolism, Conserved Sequence genetics, DNA Replication genetics, Deoxyribonuclease I metabolism, Gene Expression Regulation genetics, Gene Regulatory Networks genetics, Genome-Wide Association Study, Humans, RNA genetics, Regulatory Sequences, Nucleic Acid genetics, Species Specificity, Transcription Factors metabolism, Transcriptome genetics, Genome genetics, Genomics, Mice genetics, Molecular Sequence Annotation
Abstract

The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases.

Published
2014
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11. Comparative analysis of regulatory information and circuits across distant species.

Author

Boyle AP, Araya CL, Brdlik C, Cayting P, Cheng C, Cheng Y, Gardner K, Hillier LW, Janette J, Jiang L, Kasper D, Kawli T, Kheradpour P, Kundaje A, Li JJ, Ma L, Niu W, Rehm EJ, Rozowsky J, Slattery M, Spokony R, Terrell R, Vafeados D, Wang D, Weisdepp P, Wu YC, Xie D, Yan KK, Feingold EA, Good PJ, Pazin MJ, Huang H, Bickel PJ, Brenner SE, Reinke V, Waterston RH, Gerstein M, White KP, Kellis M, and Snyder M

Subjects
Animals, Binding Sites, Caenorhabditis elegans growth & development, Chromatin Immunoprecipitation, Conserved Sequence genetics, Drosophila melanogaster growth & development, Gene Expression Regulation, Developmental genetics, Genome genetics, Humans, Molecular Sequence Annotation, Nucleotide Motifs genetics, Organ Specificity genetics, Transcription Factors genetics, Caenorhabditis elegans genetics, Drosophila melanogaster genetics, Evolution, Molecular, Gene Expression Regulation genetics, Gene Regulatory Networks genetics, Transcription Factors metabolism
Abstract

Despite the large evolutionary distances between metazoan species, they can show remarkable commonalities in their biology, and this has helped to establish fly and worm as model organisms for human biology. Although studies of individual elements and factors have explored similarities in gene regulation, a large-scale comparative analysis of basic principles of transcriptional regulatory features is lacking. Here we map the genome-wide binding locations of 165 human, 93 worm and 52 fly transcription regulatory factors, generating a total of 1,019 data sets from diverse cell types, developmental stages, or conditions in the three species, of which 498 (48.9%) are presented here for the first time. We find that structural properties of regulatory networks are remarkably conserved and that orthologous regulatory factor families recognize similar binding motifs in vivo and show some similar co-associations. Our results suggest that gene-regulatory properties previously observed for individual factors are general principles of metazoan regulation that are remarkably well-preserved despite extensive functional divergence of individual network connections. The comparative maps of regulatory circuitry provided here will drive an improved understanding of the regulatory underpinnings of model organism biology and how these relate to human biology, development and disease.

Published
2014
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12. Comparative analysis of the transcriptome across distant species.

Author

Gerstein MB, Rozowsky J, Yan KK, Wang D, Cheng C, Brown JB, Davis CA, Hillier L, Sisu C, Li JJ, Pei B, Harmanci AO, Duff MO, Djebali S, Alexander RP, Alver BH, Auerbach R, Bell K, Bickel PJ, Boeck ME, Boley NP, Booth BW, Cherbas L, Cherbas P, Di C, Dobin A, Drenkow J, Ewing B, Fang G, Fastuca M, Feingold EA, Frankish A, Gao G, Good PJ, Guigó R, Hammonds A, Harrow J, Hoskins RA, Howald C, Hu L, Huang H, Hubbard TJ, Huynh C, Jha S, Kasper D, Kato M, Kaufman TC, Kitchen RR, Ladewig E, Lagarde J, Lai E, Leng J, Lu Z, MacCoss M, May G, McWhirter R, Merrihew G, Miller DM, Mortazavi A, Murad R, Oliver B, Olson S, Park PJ, Pazin MJ, Perrimon N, Pervouchine D, Reinke V, Reymond A, Robinson G, Samsonova A, Saunders GI, Schlesinger F, Sethi A, Slack FJ, Spencer WC, Stoiber MH, Strasbourger P, Tanzer A, Thompson OA, Wan KH, Wang G, Wang H, Watkins KL, Wen J, Wen K, Xue C, Yang L, Yip K, Zaleski C, Zhang Y, Zheng H, Brenner SE, Graveley BR, Celniker SE, Gingeras TR, and Waterston R

Subjects
Animals, Caenorhabditis elegans embryology, Caenorhabditis elegans growth & development, Chromatin genetics, Cluster Analysis, Drosophila melanogaster growth & development, Gene Expression Regulation, Developmental genetics, Histones metabolism, Humans, Larva genetics, Larva growth & development, Models, Genetic, Molecular Sequence Annotation, Promoter Regions, Genetic genetics, Pupa genetics, Pupa growth & development, RNA, Untranslated genetics, Sequence Analysis, RNA, Caenorhabditis elegans genetics, Drosophila melanogaster genetics, Gene Expression Profiling, Transcriptome genetics
Abstract

The transcriptome is the readout of the genome. Identifying common features in it across distant species can reveal fundamental principles. To this end, the ENCODE and modENCODE consortia have generated large amounts of matched RNA-sequencing data for human, worm and fly. Uniform processing and comprehensive annotation of these data allow comparison across metazoan phyla, extending beyond earlier within-phylum transcriptome comparisons and revealing ancient, conserved features. Specifically, we discover co-expression modules shared across animals, many of which are enriched in developmental genes. Moreover, we use expression patterns to align the stages in worm and fly development and find a novel pairing between worm embryo and fly pupae, in addition to the embryo-to-embryo and larvae-to-larvae pairings. Furthermore, we find that the extent of non-canonical, non-coding transcription is similar in each organism, per base pair. Finally, we find in all three organisms that the gene-expression levels, both coding and non-coding, can be quantitatively predicted from chromatin features at the promoter using a 'universal model' based on a single set of organism-independent parameters.

Published
2014
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13. Comparative analysis of metazoan chromatin organization.

Author

Ho JW, Jung YL, Liu T, Alver BH, Lee S, Ikegami K, Sohn KA, Minoda A, Tolstorukov MY, Appert A, Parker SC, Gu T, Kundaje A, Riddle NC, Bishop E, Egelhofer TA, Hu SS, Alekseyenko AA, Rechtsteiner A, Asker D, Belsky JA, Bowman SK, Chen QB, Chen RA, Day DS, Dong Y, Dose AC, Duan X, Epstein CB, Ercan S, Feingold EA, Ferrari F, Garrigues JM, Gehlenborg N, Good PJ, Haseley P, He D, Herrmann M, Hoffman MM, Jeffers TE, Kharchenko PV, Kolasinska-Zwierz P, Kotwaliwale CV, Kumar N, Langley SA, Larschan EN, Latorre I, Libbrecht MW, Lin X, Park R, Pazin MJ, Pham HN, Plachetka A, Qin B, Schwartz YB, Shoresh N, Stempor P, Vielle A, Wang C, Whittle CM, Xue H, Kingston RE, Kim JH, Bernstein BE, Dernburg AF, Pirrotta V, Kuroda MI, Noble WS, Tullius TD, Kellis M, MacAlpine DM, Strome S, Elgin SC, Liu XS, Lieb JD, Ahringer J, Karpen GH, and Park PJ

Subjects
Animals, Cell Line, Centromere genetics, Centromere metabolism, Chromatin chemistry, Chromatin Assembly and Disassembly genetics, DNA Replication genetics, Enhancer Elements, Genetic genetics, Epigenesis, Genetic, Heterochromatin chemistry, Heterochromatin genetics, Heterochromatin metabolism, Histones chemistry, Histones metabolism, Humans, Molecular Sequence Annotation, Nuclear Lamina metabolism, Nucleosomes chemistry, Nucleosomes genetics, Nucleosomes metabolism, Promoter Regions, Genetic genetics, Species Specificity, Caenorhabditis elegans cytology, Caenorhabditis elegans genetics, Chromatin genetics, Chromatin metabolism, Drosophila melanogaster cytology, Drosophila melanogaster genetics
Abstract

Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths. To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.

Published
2014
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14. Reply to Brunet and Doolittle: Both selected effect and causal role elements can influence human biology and disease.

Author

Kellis M, Wold B, Snyder MP, Bernstein BE, Kundaje A, Marinov GK, Ward LD, Birney E, Crawford GE, Dekker J, Dunham I, Elnitski LL, Farnham PJ, Feingold EA, Gerstein M, Giddings MC, Gilbert DM, Gingeras TR, Green ED, Guigo R, Hubbard T, Kent J, Lieb JD, Myers RM, Pazin MJ, Ren B, Stamatoyannopoulos J, Weng Z, White KP, and Hardison RC

Subjects
Humans, DNA genetics, Genome, Human genetics
Published
2014
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15. Defining functional DNA elements in the human genome.

Author

Kellis M, Wold B, Snyder MP, Bernstein BE, Kundaje A, Marinov GK, Ward LD, Birney E, Crawford GE, Dekker J, Dunham I, Elnitski LL, Farnham PJ, Feingold EA, Gerstein M, Giddings MC, Gilbert DM, Gingeras TR, Green ED, Guigo R, Hubbard T, Kent J, Lieb JD, Myers RM, Pazin MJ, Ren B, Stamatoyannopoulos JA, Weng Z, White KP, and Hardison RC

Subjects
Biological Evolution, Disease genetics, Humans, Regulatory Sequences, Nucleic Acid genetics, Software, DNA genetics, Genome, Human genetics
Abstract

With the completion of the human genome sequence, attention turned to identifying and annotating its functional DNA elements. As a complement to genetic and comparative genomics approaches, the Encyclopedia of DNA Elements Project was launched to contribute maps of RNA transcripts, transcriptional regulator binding sites, and chromatin states in many cell types. The resulting genome-wide data reveal sites of biochemical activity with high positional resolution and cell type specificity that facilitate studies of gene regulation and interpretation of noncoding variants associated with human disease. However, the biochemically active regions cover a much larger fraction of the genome than do evolutionarily conserved regions, raising the question of whether nonconserved but biochemically active regions are truly functional. Here, we review the strengths and limitations of biochemical, evolutionary, and genetic approaches for defining functional DNA segments, potential sources for the observed differences in estimated genomic coverage, and the biological implications of these discrepancies. We also analyze the relationship between signal intensity, genomic coverage, and evolutionary conservation. Our results reinforce the principle that each approach provides complementary information and that we need to use combinations of all three to elucidate genome function in human biology and disease.

Published
2014
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16. An encyclopedia of mouse DNA elements (Mouse ENCODE).

Author

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
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17. Integrative analysis of the Caenorhabditis elegans genome by the modENCODE project.

Author

Gerstein MB, Lu ZJ, Van Nostrand EL, Cheng C, Arshinoff BI, Liu T, Yip KY, Robilotto R, Rechtsteiner A, Ikegami K, Alves P, Chateigner A, Perry M, Morris M, Auerbach RK, Feng X, Leng J, Vielle A, Niu W, Rhrissorrakrai K, Agarwal A, Alexander RP, Barber G, Brdlik CM, Brennan J, Brouillet JJ, Carr A, Cheung MS, Clawson H, Contrino S, Dannenberg LO, Dernburg AF, Desai A, Dick L, Dosé AC, Du J, Egelhofer T, Ercan S, Euskirchen G, Ewing B, Feingold EA, Gassmann R, Good PJ, Green P, Gullier F, Gutwein M, Guyer MS, Habegger L, Han T, Henikoff JG, Henz SR, Hinrichs A, Holster H, Hyman T, Iniguez AL, Janette J, Jensen M, Kato M, Kent WJ, Kephart E, Khivansara V, Khurana E, Kim JK, Kolasinska-Zwierz P, Lai EC, Latorre I, Leahey A, Lewis S, Lloyd P, Lochovsky L, Lowdon RF, Lubling Y, Lyne R, MacCoss M, Mackowiak SD, Mangone M, McKay S, Mecenas D, Merrihew G, Miller DM 3rd, Muroyama A, Murray JI, Ooi SL, Pham H, Phippen T, Preston EA, Rajewsky N, Rätsch G, Rosenbaum H, Rozowsky J, Rutherford K, Ruzanov P, Sarov M, Sasidharan R, Sboner A, Scheid P, Segal E, Shin H, Shou C, Slack FJ, Slightam C, Smith R, Spencer WC, Stinson EO, Taing S, Takasaki T, Vafeados D, Voronina K, Wang G, Washington NL, Whittle CM, Wu B, Yan KK, Zeller G, Zha Z, Zhong M, Zhou X, Ahringer J, Strome S, Gunsalus KC, Micklem G, Liu XS, Reinke V, Kim SK, Hillier LW, Henikoff S, Piano F, Snyder M, Stein L, Lieb JD, and Waterston RH

Subjects
Animals, Caenorhabditis elegans growth & development, Caenorhabditis elegans metabolism, Caenorhabditis elegans Proteins genetics, Caenorhabditis elegans Proteins metabolism, Chromatin genetics, Chromatin metabolism, Chromatin ultrastructure, Computational Biology methods, Conserved Sequence, Evolution, Molecular, Gene Regulatory Networks, Genes, Helminth, Genomics methods, Histones metabolism, Models, Genetic, RNA, Helminth genetics, RNA, Helminth metabolism, RNA, Untranslated genetics, RNA, Untranslated metabolism, Regulatory Sequences, Nucleic Acid, Transcription Factors genetics, Transcription Factors metabolism, Caenorhabditis elegans genetics, Chromosomes genetics, Chromosomes metabolism, Chromosomes ultrastructure, Gene Expression Profiling, Gene Expression Regulation, Genome, Helminth, Molecular Sequence Annotation
Abstract

We systematically generated large-scale data sets to improve genome annotation for the nematode Caenorhabditis elegans, a key model organism. These data sets include transcriptome profiling across a developmental time course, genome-wide identification of transcription factor-binding sites, and maps of chromatin organization. From this, we created more complete and accurate gene models, including alternative splice forms and candidate noncoding RNAs. We constructed hierarchical networks of transcription factor-binding and microRNA interactions and discovered chromosomal locations bound by an unusually large number of transcription factors. Different patterns of chromatin composition and histone modification were revealed between chromosome arms and centers, with similarly prominent differences between autosomes and the X chromosome. Integrating data types, we built statistical models relating chromatin, transcription factor binding, and gene expression. Overall, our analyses ascribed putative functions to most of the conserved genome.

Published
2010
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18. The completion of the Mammalian Gene Collection (MGC).

Author

Temple G, Gerhard DS, Rasooly R, Feingold EA, Good PJ, Robinson C, Mandich A, Derge JG, Lewis J, Shoaf D, Collins FS, Jang W, Wagner L, Shenmen CM, Misquitta L, Schaefer CF, Buetow KH, Bonner TI, Yankie L, Ward M, Phan L, Astashyn A, Brown G, Farrell C, Hart J, Landrum M, Maidak BL, Murphy M, Murphy T, Rajput B, Riddick L, Webb D, Weber J, Wu W, Pruitt KD, Maglott D, Siepel A, Brejova B, Diekhans M, Harte R, Baertsch R, Kent J, Haussler D, Brent M, Langton L, Comstock CL, Stevens M, Wei C, van Baren MJ, Salehi-Ashtiani K, Murray RR, Ghamsari L, Mello E, Lin C, Pennacchio C, Schreiber K, Shapiro N, Marsh A, Pardes E, Moore T, Lebeau A, Muratet M, Simmons B, Kloske D, Sieja S, Hudson J, Sethupathy P, Brownstein M, Bhat N, Lazar J, Jacob H, Gruber CE, Smith MR, McPherson J, Garcia AM, Gunaratne PH, Wu J, Muzny D, Gibbs RA, Young AC, Bouffard GG, Blakesley RW, Mullikin J, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Hirst M, Zeng T, Tse K, Moksa M, Deng M, Ma K, Mah D, Pang J, Taylor G, Chuah E, Deng A, Fichter K, Go A, Lee S, Wang J, Griffith M, Morin R, Moore RA, Mayo M, Munro S, Wagner S, Jones SJ, Holt RA, Marra MA, Lu S, Yang S, Hartigan J, Graf M, Wagner R, Letovksy S, Pulido JC, Robison K, Esposito D, Hartley J, Wall VE, Hopkins RF, Ohara O, and Wiemann S

Subjects
Animals, DNA biosynthesis, Humans, Mice, National Institutes of Health (U.S.), Rats, Reverse Transcriptase Polymerase Chain Reaction, United States, Cloning, Molecular methods, Computational Biology methods, DNA, Complementary genetics, Gene Library, Genes genetics, Mammals genetics
Abstract

Since its start, the Mammalian Gene Collection (MGC) has sought to provide at least one full-protein-coding sequence cDNA clone for every human and mouse gene with a RefSeq transcript, and at least 6200 rat genes. The MGC cloning effort initially relied on random expressed sequence tag screening of cDNA libraries. Here, we summarize our recent progress using directed RT-PCR cloning and DNA synthesis. The MGC now contains clones with the entire protein-coding sequence for 92% of human and 89% of mouse genes with curated RefSeq (NM-accession) transcripts, and for 97% of human and 96% of mouse genes with curated RefSeq transcripts that have one or more PubMed publications, in addition to clones for more than 6300 rat genes. These high-quality MGC clones and their sequences are accessible without restriction to researchers worldwide.

Published
2009
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19. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project.

Author

Birney E, Stamatoyannopoulos JA, Dutta A, Guigó R, Gingeras TR, Margulies EH, Weng Z, Snyder M, Dermitzakis ET, Thurman RE, Kuehn MS, Taylor CM, Neph S, Koch CM, Asthana S, Malhotra A, Adzhubei I, Greenbaum JA, Andrews RM, Flicek P, Boyle PJ, Cao H, Carter NP, Clelland GK, Davis S, Day N, Dhami P, Dillon SC, Dorschner MO, Fiegler H, Giresi PG, Goldy J, Hawrylycz M, Haydock A, Humbert R, James KD, Johnson BE, Johnson EM, Frum TT, Rosenzweig ER, Karnani N, Lee K, Lefebvre GC, Navas PA, Neri F, Parker SC, Sabo PJ, Sandstrom R, Shafer A, Vetrie D, Weaver M, Wilcox S, Yu M, Collins FS, Dekker J, Lieb JD, Tullius TD, Crawford GE, Sunyaev S, Noble WS, Dunham I, Denoeud F, Reymond A, Kapranov P, Rozowsky J, Zheng D, Castelo R, Frankish A, Harrow J, Ghosh S, Sandelin A, Hofacker IL, Baertsch R, Keefe D, Dike S, Cheng J, Hirsch HA, Sekinger EA, Lagarde J, Abril JF, Shahab A, Flamm C, Fried C, Hackermüller J, Hertel J, Lindemeyer M, Missal K, Tanzer A, Washietl S, Korbel J, Emanuelsson O, Pedersen JS, Holroyd N, Taylor R, Swarbreck D, Matthews N, Dickson MC, Thomas DJ, Weirauch MT, Gilbert J, Drenkow J, Bell I, Zhao X, Srinivasan KG, Sung WK, Ooi HS, Chiu KP, Foissac S, Alioto T, Brent M, Pachter L, Tress ML, Valencia A, Choo SW, Choo CY, Ucla C, Manzano C, Wyss C, Cheung E, Clark TG, Brown JB, Ganesh M, Patel S, Tammana H, Chrast J, Henrichsen CN, Kai C, Kawai J, Nagalakshmi U, Wu J, Lian Z, Lian J, Newburger P, Zhang X, Bickel P, Mattick JS, Carninci P, Hayashizaki Y, Weissman S, Hubbard T, Myers RM, Rogers J, Stadler PF, Lowe TM, Wei CL, Ruan Y, Struhl K, Gerstein M, Antonarakis SE, Fu Y, Green ED, Karaöz U, Siepel A, Taylor J, Liefer LA, Wetterstrand KA, Good PJ, Feingold EA, Guyer MS, Cooper GM, Asimenos G, Dewey CN, Hou M, Nikolaev S, Montoya-Burgos JI, Löytynoja A, Whelan S, Pardi F, Massingham T, Huang H, Zhang NR, Holmes I, Mullikin JC, Ureta-Vidal A, Paten B, Seringhaus M, Church D, Rosenbloom K, Kent WJ, Stone EA, Batzoglou S, Goldman N, Hardison RC, Haussler D, Miller W, Sidow A, Trinklein ND, Zhang ZD, Barrera L, Stuart R, King DC, Ameur A, Enroth S, Bieda MC, Kim J, Bhinge AA, Jiang N, Liu J, Yao F, Vega VB, Lee CW, Ng P, Shahab A, Yang A, Moqtaderi Z, Zhu Z, Xu X, Squazzo S, Oberley MJ, Inman D, Singer MA, Richmond TA, Munn KJ, Rada-Iglesias A, Wallerman O, Komorowski J, Fowler JC, Couttet P, Bruce AW, Dovey OM, Ellis PD, Langford CF, Nix DA, Euskirchen G, Hartman S, Urban AE, Kraus P, Van Calcar S, Heintzman N, Kim TH, Wang K, Qu C, Hon G, Luna R, Glass CK, Rosenfeld MG, Aldred SF, Cooper SJ, Halees A, Lin JM, Shulha HP, Zhang X, Xu M, Haidar JN, Yu Y, Ruan Y, Iyer VR, Green RD, Wadelius C, Farnham PJ, Ren B, Harte RA, Hinrichs AS, Trumbower H, Clawson H, Hillman-Jackson J, Zweig AS, Smith K, Thakkapallayil A, Barber G, Kuhn RM, Karolchik D, Armengol L, Bird CP, de Bakker PI, Kern AD, Lopez-Bigas N, Martin JD, Stranger BE, Woodroffe A, Davydov E, Dimas A, Eyras E, Hallgrímsdóttir IB, Huppert J, Zody MC, Abecasis GR, Estivill X, Bouffard GG, Guan X, Hansen NF, Idol JR, Maduro VV, Maskeri B, McDowell JC, Park M, Thomas PJ, Young AC, Blakesley RW, Muzny DM, Sodergren E, Wheeler DA, Worley KC, Jiang H, Weinstock GM, Gibbs RA, Graves T, Fulton R, Mardis ER, Wilson RK, Clamp M, Cuff J, Gnerre S, Jaffe DB, Chang JL, Lindblad-Toh K, Lander ES, Koriabine M, Nefedov M, Osoegawa K, Yoshinaga Y, Zhu B, and de Jong PJ

Subjects
Chromatin genetics, Chromatin metabolism, Chromatin Immunoprecipitation, Conserved Sequence genetics, DNA Replication, Evolution, Molecular, Exons genetics, Genetic Variation genetics, Heterozygote, Histones metabolism, Humans, Pilot Projects, Protein Binding, RNA, Messenger genetics, RNA, Untranslated genetics, Transcription Factors metabolism, Transcription Initiation Site, Genome, Human genetics, Genomics, Regulatory Sequences, Nucleic Acid genetics, Transcription, Genetic genetics
Abstract

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

Published
2007
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20. The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

Author

Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, and Malek J

Subjects
Animals, Computational Biology, DNA Primers, Humans, Mice, National Institutes of Health (U.S.), Rats, United States, Xenopus laevis genetics, Zebrafish genetics, Cloning, Molecular methods, DNA, Complementary genetics, DNA, Complementary metabolism, Gene Library, Open Reading Frames physiology
Abstract

The National Institutes of Health's Mammalian Gene Collection (MGC) project was designed to generate and sequence a publicly accessible cDNA resource containing a complete open reading frame (ORF) for every human and mouse gene. The project initially used a random strategy to select clones from a large number of cDNA libraries from diverse tissues. Candidate clones were chosen based on 5'-EST sequences, and then fully sequenced to high accuracy and analyzed by algorithms developed for this project. Currently, more than 11,000 human and 10,000 mouse genes are represented in MGC by at least one clone with a full ORF. The random selection approach is now reaching a saturation point, and a transition to protocols targeted at the missing transcripts is now required to complete the mouse and human collections. Comparison of the sequence of the MGC clones to reference genome sequences reveals that most cDNA clones are of very high sequence quality, although it is likely that some cDNAs may carry missense variants as a consequence of experimental artifact, such as PCR, cloning, or reverse transcriptase errors. Recently, a rat cDNA component was added to the project, and ongoing frog (Xenopus) and zebrafish (Danio) cDNA projects were expanded to take advantage of the high-throughput MGC pipeline.

Published
2004
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21. Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.

Author

Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L, Shenmen CM, Schuler GD, Altschul SF, Zeeberg B, Buetow KH, Schaefer CF, Bhat NK, Hopkins RF, Jordan H, Moore T, Max SI, Wang J, Hsieh F, Diatchenko L, Marusina K, Farmer AA, Rubin GM, Hong L, Stapleton M, Soares MB, Bonaldo MF, Casavant TL, Scheetz TE, Brownstein MJ, Usdin TB, Toshiyuki S, Carninci P, Prange C, Raha SS, Loquellano NA, Peters GJ, Abramson RD, Mullahy SJ, Bosak SA, McEwan PJ, McKernan KJ, Malek JA, Gunaratne PH, Richards S, Worley KC, Hale S, Garcia AM, Gay LJ, Hulyk SW, Villalon DK, Muzny DM, Sodergren EJ, Lu X, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madan A, Young AC, Shevchenko Y, Bouffard GG, Blakesley RW, Touchman JW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Krzywinski MI, Skalska U, Smailus DE, Schnerch A, Schein JE, Jones SJ, and Marra MA

Subjects
Algorithms, Animals, DNA, Complementary analysis, Gene Library, Humans, Mice, Open Reading Frames, DNA, Complementary chemistry, Sequence Analysis, DNA
Abstract

The National Institutes of Health Mammalian Gene Collection (MGC) Program is a multiinstitutional effort to identify and sequence a cDNA clone containing a complete ORF for each human and mouse gene. ESTs were generated from libraries enriched for full-length cDNAs and analyzed to identify candidate full-ORF clones, which then were sequenced to high accuracy. The MGC has currently sequenced and verified the full ORF for a nonredundant set of >9,000 human and >6,000 mouse genes. Candidate full-ORF clones for an additional 7,800 human and 3,500 mouse genes also have been identified. All MGC sequences and clones are available without restriction through public databases and clone distribution networks (see http:mgc.nci.nih.gov).

Published
2002
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22. The mammalian gene collection.

Author

Strausberg RL, Feingold EA, Klausner RD, and Collins FS

Subjects
Animals, Base Sequence, Computational Biology, DNA, Complementary, Databases, Factual, Expressed Sequence Tags, Humans, Mice, National Institutes of Health (U.S.), Private Sector, Public Sector, United States, Gene Library, Genome, Genome, Human, Mammals genetics, Sequence Analysis, DNA
Abstract

The Mammalian Gene Collection (MGC) project is a new effort by the NIH to generate full-length complementary DNA (cDNA) resources. This project will provide publicly accessible resources to the full research community. The MGC project entails the production of libraries, sequencing, and database and repository development, as well as the support of library construction, sequencing, and analytic technologies dedicated to the goal of obtaining a full set of human and other mammalian full-length (open reading frame) sequences and clones of expressed genes.

Published
1999
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23. An olfactory receptor gene is located in the extended human beta-globin gene cluster and is expressed in erythroid cells.

Author

Feingold EA, Penny LA, Nienhuis AW, and Forget BG

Subjects
Amino Acid Sequence, Animals, Base Sequence, Cell Line, DNA, Fetal Hemoglobin, Gene Deletion, Gene Expression, Hemoglobinopathies genetics, Humans, Mice, Molecular Sequence Data, Reverse Transcriptase Polymerase Chain Reaction, Ribonucleases, Sequence Analysis, DNA, Tumor Cells, Cultured, Chromosomes, Human, Pair 11, Globins genetics, Multigene Family, Receptors, Odorant genetics
Abstract

An olfactory receptor gene was identified near the 3' breakpoint of a naturally occurring deletion (HPFH-1) in the human beta-globin gene cluster on chromosome 11p15.5. The gene encodes an amino acid sequence that is 40 to 51% identical to that of a set of olfactory receptors that have only recently been identified as a distinct family of receptors. There are two orthologous genes in the mouse that encode amino acid sequences that are 73 and 71% identical, respectively, to that encoded by the human gene. This olfactory receptor gene is expressed at the RNA level in human and murine erythroid cells at all stages of development. This aberrant expression is probably due to the location of the gene in the transcriptionally active chromatin domain of the extended beta-globin gene cluster in erythroid cells., (Copyright 1999 Academic Press.)

Published
1999
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24. Molecular studies of mutations that increase Hb F production in man.

Author

Forget BG, Tuan D, Newman MV, Feingold EA, Collins F, Fukumaki Y, Jagadeeswaran P, and Weissman SM

Subjects
Biological Evolution, Chromosome Deletion, Chromosome Mapping, Cloning, Molecular, Gene Expression Regulation, Humans, Mutation, Polymorphism, Genetic, Fetal Hemoglobin genetics, Thalassemia genetics
Published
1983

25. Analysis of mutations associated with deletion and nondeletion hereditary persistence of fetal hemoglobin.

Author

Feingold EA, Collins FS, Metherall JE, Stoeckert CJ Jr, Weissman SM, and Forget BG

Subjects
Acetyltransferases genetics, Adult, Animals, Base Sequence, Cell Line, Chloramphenicol O-Acetyltransferase, DNA Restriction Enzymes metabolism, DNA, Recombinant, Female, Haplorhini, HeLa Cells, Humans, Kidney cytology, Phenotype, Plasmids, Pregnancy, Simian virus 40 genetics, Transfection, Chromosome Deletion, Fetal Hemoglobin genetics, Hemoglobinopathies genetics, Mutation
Published
1985

26. Molecular analysis of deletion and nondeletion hereditary persistence of fetal hemoglobin and identification of a new mutation causing beta-thalassemia.

Author

Feingold EA, Collins FS, Metherall JE, Stoeckert CJ Jr, Weissman SM, and Forget BG

Subjects
Animals, Base Sequence, Cell Line, Chromosome Mapping, DNA genetics, DNA Restriction Enzymes, Fetal Hemoglobin metabolism, Greece, Mice, Transfection, Chromosome Deletion, Fetal Hemoglobin genetics, Mutation, Thalassemia genetics
Published
1985
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