Search

Your search keyword '"Klein, Isaac A."' showing total 157 results
Start Over Author "Klein, Isaac A."
157 results on '"Klein, Isaac A."'

2. The transcription factor PAX8 promotes angiogenesis in ovarian cancer through interaction with SOX17.

Author

Chaves-Moreira, Daniele, Mitchell, Marilyn, Arruza, Cristina, Rawat, Priyanka, Sidoli, Simone, Nameki, Robbin, Reddy, Jessica, Corona, Rosario, Afeyan, Lena, Klein, Isaac, Ma, Sisi, Winterhoff, Boris, Konecny, Gottfried, Garcia, Benjamin, Brady, Donita, Lawrenson, Kate, Morin, Patrice, and Drapkin, Ronny

Subjects
Animals, Fallopian Tubes, Female, HMGB Proteins, Humans, Mice, Neoplasm Grading, Ovarian Neoplasms, PAX8 Transcription Factor, SOXF Transcription Factors, Transcription Factors
Abstract

PAX8 is a master transcription factor that is essential during embryogenesis and promotes neoplastic growth. It is expressed by the secretory cells lining the female reproductive tract, and its deletion during development results in atresia of reproductive tract organs. Nearly all ovarian carcinomas express PAX8, and its knockdown results in apoptosis of ovarian cancer cells. To explore the role of PAX8 in these tissues, we purified the PAX8 protein complex from nonmalignant fallopian tube cells and high-grade serous ovarian carcinoma cell lines. We found that PAX8 was a member of a large chromatin remodeling complex and preferentially interacted with SOX17, another developmental transcription factor. Depleting either PAX8 or SOX17 from cancer cells altered the expression of factors involved in angiogenesis and functionally disrupted tubule and capillary formation in cell culture and mouse models. PAX8 and SOX17 in ovarian cancer cells promoted the secretion of angiogenic factors by suppressing the expression of SERPINE1, which encodes a proteinase inhibitor with antiangiogenic effects. The findings reveal a non-cell-autonomous function of these transcription factors in regulating angiogenesis in ovarian cancer.

Published
2022

3. Predicting master transcription factors from pan-cancer expression data

Author

Reddy, Jessica, Fonseca, Marcos AS, Corona, Rosario I, Nameki, Robbin, Segato Dezem, Felipe, Klein, Isaac A, Chang, Heidi, Chaves-Moreira, Daniele, Afeyan, Lena K, Malta, Tathiane M, Lin, Xianzhi, Abbasi, Forough, Font-Tello, Alba, Sabedot, Thais, Cejas, Paloma, Rodríguez-Malavé, Norma, Seo, Ji-Heui, Lin, De-Chen, Matulonis, Ursula, Karlan, Beth Y, Gayther, Simon A, Pasaniuc, Bogdan, Gusev, Alexander, Noushmehr, Houtan, Long, Henry, Freedman, Matthew L, Drapkin, Ronny, Young, Richard A, Abraham, Brian J, and Lawrenson, Kate

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Rare Diseases, Genetics, Ovarian Cancer, Human Genome
Abstract

Critical developmental “master transcription factors” (MTFs) can be subverted during tumorigenesis to control oncogenic transcriptional programs. Current approaches to identifying MTFs rely on ChIP-seq data, which is unavailable for many cancers. We developed the CaCTS (Cancer Core Transcription factor Specificity) algorithm to prioritize candidate MTFs using pan-cancer RNA sequencing data. CaCTS identified candidate MTFs across 34 tumor types and 140 subtypes including predictions for cancer types/subtypes for which MTFs are unknown, including e.g. PAX8, SOX17, and MECOM as candidates in ovarian cancer (OvCa). In OvCa cells, consistent with known MTF properties, these factors are required for viability, lie proximal to superenhancers, co-occupy regulatory elements globally, co-bind loci encoding OvCa biomarkers, and are sensitive to pharmacologic inhibition of transcription. Our predictions of MTFs, especially for tumor types with limited understanding of transcriptional drivers, pave the way to therapeutic targeting of MTFs in a broad spectrum of cancers.

Published
2021

8. Coactivator condensation at super-enhancers links phase separation and gene control

Author

Sabari, Benjamin R., Dall’Agnese, Alessandra, Boija, Ann, Klein, Isaac A., Coffey, Eliot L., Shrinivas, Krishna, Abraham, Brian J., Hannett, Nancy M., Zamudio, Alicia V., Manteiga, John C., Li, Charles H., Guo, Yang E., Day, Daniel S., Schuijers, Jurian, Vasile, Eliza, Malik, Sohail, Hnisz, Denes, Lee, Tong Ihn, Cisse, Ibrahim I., Roeder, Robert G., Sharp, Phillip A., Chakraborty, Arup K., and Young, Richard A.

Published
2018

11. Parallel Automated Flow Synthesis of Covalent Protein Complexes That Can Inhibit MYC-Driven Transcription

Author

Massachusetts Institute of Technology. Department of Chemistry, Massachusetts Institute of Technology. Center for Environmental Health Sciences, Koch Institute for Integrative Cancer Research at MIT, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology. Department of Biology, Pomplun, Sebastian, Jbara, Muhammad, Schissel, Carly K, Wilson Hawken, Susana, Boija, Ann, Li, Charles, Klein, Isaac, Pentelute, Bradley L, Massachusetts Institute of Technology. Department of Chemistry, Massachusetts Institute of Technology. Center for Environmental Health Sciences, Koch Institute for Integrative Cancer Research at MIT, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology. Department of Biology, Pomplun, Sebastian, Jbara, Muhammad, Schissel, Carly K, Wilson Hawken, Susana, Boija, Ann, Li, Charles, Klein, Isaac, and Pentelute, Bradley L

Abstract

Dysregulation of the transcription factor MYC is involved in many human cancers. The dimeric transcription factor complexes of MYC/MAX and MAX/MAX activate or inhibit, respectively, gene transcription upon binding to the same enhancer box DNA. Targeting these complexes in cancer is a long-standing challenge. Inspired by the inhibitory activity of the MAX/MAX dimer, we engineered covalently linked, synthetic homo- and heterodimeric protein complexes to attenuate oncogenic MYC-driven transcription. We prepared the covalent protein complexes (∼20 kDa, 167-231 residues) in a single shot via parallel automated flow synthesis in hours. The stabilized covalent dimers display DNA binding activity, are intrinsically cell-penetrant, and inhibit cancer cell proliferation in different cell lines. RNA sequencing and gene set enrichment analysis in A549 cancer cells confirmed that the synthetic dimers interfere with MYC-driven transcription. Our results demonstrate the potential of automated flow technology to rapidly deliver engineered synthetic protein complex mimetics that can serve as a starting point in developing inhibitors of MYC-driven cancer cell growth.

Published
2022

12. Partitioning of cancer therapeutics in nuclear condensates

Author

Klein, Isaac A., Boija, Ann, Afeyan, Lena K., Hawken, Susana Wilson, Fan, Mengyang, Dall'Agnese, Alessandra, Oksuz, Ozgur, Henninger, Jonathan E., Shrinivas, Krishna, Sabari, Benjamin R., Sagi, Ido, Clark, Victoria E., Platt, Jesse M., Kar, Mrityunjoy, McCall, Patrick M., Zamudio, Alicia V., Manteiga, John C., Coffey, Eliot L., Li, Charles H., Hannett, Nancy M., Guo, Yang Eric, Decker, Tim-Michael, Lee, Tong Ihn, Zhang, Tinghu, Weng, Jing-Ke, Taatjes, Dylan J., Chakraborty, Arup, Sharp, Phillip A., Chang, Young Tae, Hyman, Anthony A., Gray, Nathanael S., Young, Richard A., Klein, Isaac A., Boija, Ann, Afeyan, Lena K., Hawken, Susana Wilson, Fan, Mengyang, Dall'Agnese, Alessandra, Oksuz, Ozgur, Henninger, Jonathan E., Shrinivas, Krishna, Sabari, Benjamin R., Sagi, Ido, Clark, Victoria E., Platt, Jesse M., Kar, Mrityunjoy, McCall, Patrick M., Zamudio, Alicia V., Manteiga, John C., Coffey, Eliot L., Li, Charles H., Hannett, Nancy M., Guo, Yang Eric, Decker, Tim-Michael, Lee, Tong Ihn, Zhang, Tinghu, Weng, Jing-Ke, Taatjes, Dylan J., Chakraborty, Arup, Sharp, Phillip A., Chang, Young Tae, Hyman, Anthony A., Gray, Nathanael S., and Young, Richard A.

Abstract

© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.

Published
2022

19. lncRNA DIGIT and BRD3 protein form phase-separated condensates to regulate endoderm differentiation

Author

Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Daneshvar, Kaveh, Ardehali, M Behfar, Klein, Isaac A, Hsieh, Fu-Kai, Kratkiewicz, Arcadia J, Mahpour, Amin, Cancelliere, Sabrina OL, Zhou, Chan, Cook, Brett M, Li, Wenyang, Pondick, Joshua V, Gupta, Sweta K, Moran, Sean P, Young, Richard A, Kingston, Robert E, Mullen, Alan C, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Daneshvar, Kaveh, Ardehali, M Behfar, Klein, Isaac A, Hsieh, Fu-Kai, Kratkiewicz, Arcadia J, Mahpour, Amin, Cancelliere, Sabrina OL, Zhou, Chan, Cook, Brett M, Li, Wenyang, Pondick, Joshua V, Gupta, Sweta K, Moran, Sean P, Young, Richard A, Kingston, Robert E, and Mullen, Alan C

Abstract

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Cooperation between DNA, RNA and protein regulates gene expression and controls differentiation through interactions that connect regions of nucleic acids and protein domains and through the assembly of biomolecular condensates. Here, we report that endoderm differentiation is regulated by the interaction between the long non-coding RNA (lncRNA) DIGIT and the bromodomain and extraterminal domain protein BRD3. BRD3 forms phase-separated condensates of which the formation is promoted by DIGIT, occupies enhancers of endoderm transcription factors and is required for endoderm differentiation. BRD3 binds to histone H3 acetylated at lysine 18 (H3K18ac) in vitro and co-occupies the genome with H3K18ac. DIGIT is also enriched in regions of H3K18ac, and the depletion of DIGIT results in decreased recruitment of BRD3 to these regions. Our findings show that cooperation between DIGIT and BRD3 at regions of H3K18ac regulates the transcription factors that drive endoderm differentiation and suggest that protein–lncRNA phase-separated condensates have a broader role as regulators of transcription.

Published
2021

20. Biomolecular Condensates and Cancer

Author

Massachusetts Institute of Technology. Department of Biology, Boija, Ann, Klein, Isaac A., Young, Richard A., Massachusetts Institute of Technology. Department of Biology, Boija, Ann, Klein, Isaac A., and Young, Richard A.

Abstract

Malignant transformation is characterized by dysregulation of diverse cellular processes that have been the subject of detailed genetic, biochemical, and structural studies, but only recently has evidence emerged that many of these processes occur in the context of biomolecular condensates. Condensates are membrane-less bodies, often formed by liquid-liquid phase separation, that compartmentalize protein and RNA molecules with related functions. New insights from condensate studies portend a profound transformation in our understanding of cellular dysregulation in cancer. Here we summarize key features of biomolecular condensates, note where they have been implicated—or will likely be implicated—in oncogenesis, describe evidence that the pharmacodynamics of cancer therapeutics can be greatly influenced by condensates, and discuss some of the questions that must be addressed to further advance our understanding and treatment of cancer., NIH (Grants GM123511, CA213333 and CA155258)

Published
2021

21. Enhancer Features that Drive Formation of Transcriptional Condensates

Author

Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Department of Physics, Ragon Institute of MGH, MIT and Harvard, Massachusetts Institute of Technology. Department of Chemistry, Shrinivas, Krishna, Sabari, Benjamin R, Coffey, Eliot L, Klein, Isaac A, Boija, Ann, Zamudio, Alicia V, Schuijers, Jurian, Hannett, Nancy M, Sharp, Phillip A, Young, Richard A, Chakraborty, Arup K, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology. Department of Biology, Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology. Department of Physics, Ragon Institute of MGH, MIT and Harvard, Massachusetts Institute of Technology. Department of Chemistry, Shrinivas, Krishna, Sabari, Benjamin R, Coffey, Eliot L, Klein, Isaac A, Boija, Ann, Zamudio, Alicia V, Schuijers, Jurian, Hannett, Nancy M, Sharp, Phillip A, Young, Richard A, and Chakraborty, Arup K

Abstract

© 2019 Elsevier Inc. Enhancers are DNA elements that are bound by transcription factors (TFs), which recruit coactivators and the transcriptional machinery to genes. Phase-separated condensates of TFs and coactivators have been implicated in assembling the transcription machinery at particular enhancers, yet the role of DNA sequence in this process has not been explored. We show that DNA sequences encoding TF binding site number, density, and affinity above sharply defined thresholds drive condensation of TFs and coactivators. A combination of specific structured (TF-DNA) and weak multivalent (TF-coactivator) interactions allows for condensates to form at particular genomic loci determined by the DNA sequence and the complement of expressed TFs. DNA features found to drive condensation promote enhancer activity and transcription in cells. Our study provides a framework to understand how the genome can scaffold transcriptional condensates at specific loci and how the universal phenomenon of phase separation might regulate this process. Shrinivas et al. demonstrate that specific types of motif compositions encoded in DNA drive localized formation of transcriptional condensates. These findings explain how phase separation can occur at specific genomic locations and shed light on why only some genomic loci become highly active enhancers.

Published
2021

22. DNA damage defines sites of recurrent chromosomal translocations in B lymphocytes

Author

Hakim, Ofir, Resch, Wolfgang, Yamane, Arito, Klein, Isaac, Kieffer-Kwon, Kyong-Rim, Jankovic, Mila, Oliveira, Thiago, Bothmer, Anne, Voss, Ty C., Ansarah-Sobrinho, Camilo, Mathe, Ewy, Liang, Genqing, Cobell, Jesse, Nakahashi, Hirotaka, Robbiani, Davide F., Nussenzweig, Andre, Hager, Gordon L., Nussenzweig, Michel C., and Casellas, Rafael

Subjects
Translocation (Genetics) -- Physiological aspects -- Health aspects, B cells -- Genetic aspects -- Health aspects, DNA damage -- Physiological aspects -- Health aspects, Cancer -- Development and progression -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Recurrent chromosomal translocations underlie both haematopoietic and solid tumours. Their origin has been ascribed to selection of random rearrangements, targeted DNA damage, or frequent nuclear interactions between translocation partners; however, the relative contribution of each of these elements has not been measured directly or on a large scale. Here we examine the role of nuclear architecture and frequency of DNA damage in the genesis of chromosomal translocations by measuring these parameters simultaneously in cultured mouse B lymphocytes. In the absence of recurrent DNA damage, translocations between Igh or Myc and all other genes are directly related to their contact frequency. Conversely, translocations associated with recurrent site-directed DNA damage are proportional to the rate of DNA break formation, as measured by replication protein A accumulation at the site of damage. Thus, non-targeted rearrangements reflect nuclear organization whereas DNA break formation governs the location and frequency of recurrent translocations, including those driving B-cell malignancies., Most cancers bear cytogenetic abnormalities including chromosomal translocations and rearrangements (1). Although translocations and rearrangements are central to the development of cancer, their origins are poorly understood. One possibility is [...]

Published
2012
Full Text
View/download PDF

23. Partitioning of cancer therapeutics in nuclear condensates.

Author

Klein, Isaac, primary, Boija, Ann, additional, Afeyan, Lena, additional, Hawken, Susana, additional, Fan, Mengyang, additional, Taatjes, Dylan, additional, Chakraborty, Arup, additional, Sharp, Phillip, additional, Chang, Young Tae, additional, Hyman, Anthony, additional, Gray, Nathanael, additional, and Young, Richard, additional

Published
2021
Full Text
View/download PDF

24. Impact of Cancer History on Outcomes Among Hospitalized Patients with COVID-19

Author

Klein, Isaac A., primary, Rosenberg, Shoshana M., additional, Reynolds, Kerry L., additional, Zubiri, Leyre, additional, Rosovsky, Rachel, additional, Piper-Vallillo, Andrew J., additional, Gao, Xin, additional, Boland, Genevieve, additional, Bardia, Aditya, additional, Gaither, Rachel, additional, Freeman, Hannah, additional, Kirkner, Gregory J., additional, Rhee, Chanu, additional, Klompas, Michael, additional, Baker, Meghan A., additional, Wadleigh, Martha, additional, Winer, Eric P., additional, Kotton, Camille N., additional, and Partridge, Ann H., additional

Published
2021
Full Text
View/download PDF

25. Impact of COVID-19 on Patients with Cancer Receiving Immune Checkpoint Inhibitors

Author

Bui, Ai-Tram N., primary, Tyan, Kevin, additional, Giobbie-Hurder, Anita, additional, Klein, Isaac A., additional, Manos, Michael P., additional, Zubiri, Leyre, additional, Reynolds, Kerry, additional, Grover, Shilpa, additional, Weinhouse, Gerald L., additional, Ott, Patrick A., additional, LeBoeuf, Nicole R., additional, and Rahma, Osama, additional

Published
2021
Full Text
View/download PDF

26. Rag mutations reveal robust alternative end joining

Author

Corneo, Barbara, Wendland, Rebecca L., Deriano, Ludovic, Cui, Xiaoping, Klein, Isaac A., Wong, Serre-Yu, Arnal, Suzzette, Holub, Abigail J., Weller, Geoffrey R., Pancake, Bette A., Shah, Sundeep, Brandt, Vicky L., Meek, Katheryn, and Roth, David B.

Subjects
Gene mutations -- Research, DNA repair -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation, Research
Abstract

Mammalian cells repair DNA double-strand breaks (DSBs) through either homologous recombination or non-homologous end joining (NHEJ). V(D)J recombination, a cut-and-paste mechanism for generating diversity in antigen receptors, relies on NHEJ [...]

Published
2007

27. Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

Author

Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Klein, Isaac A., Sabari, Benjamin R., Dall’Agnese, Alessandra, Coffey, Eliot L., Zamudio, Alicia V., Manteiga, John C., Hannett, Nancy M., Abraham, Brian J., Afeyan, Lena K., Guo, Yang E., Schuijers, Jurian, Lee, Tong Ihn, Taatjes, Dylan J., Young, Richard A., Shrinivas, Krishna,Ph. D.Massachusetts Institute of Technology., Li, Charles H., Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Klein, Isaac A., Sabari, Benjamin R., Dall’Agnese, Alessandra, Coffey, Eliot L., Zamudio, Alicia V., Manteiga, John C., Hannett, Nancy M., Abraham, Brian J., Afeyan, Lena K., Guo, Yang E., Schuijers, Jurian, Lee, Tong Ihn, Taatjes, Dylan J., Young, Richard A., Shrinivas, Krishna,Ph. D.Massachusetts Institute of Technology., and Li, Charles H.

Abstract

Gene expression is controlled by transcription factors (TFs) that consist of DNA-binding domains (DBDs) and activation domains (ADs). The DBDs have been well characterized, but little is known about the mechanisms by which ADs effect gene activation. Here, we report that diverse ADs form phase-separated condensates with the Mediator coactivator. For the OCT4 and GCN4 TFs, we show that the ability to form phase-separated droplets with Mediator in vitro and the ability to activate genes in vivo are dependent on the same amino acid residues. For the estrogen receptor (ER), a ligand-dependent activator, we show that estrogen enhances phase separation with Mediator, again linking phase separation with gene activation. These results suggest that diverse TFs can interact with Mediator through the phase-separating capacity of their ADs and that formation of condensates with Mediator is involved in gene activation., National Institutes of Health (U.S.) (Grant GM123511), National Institutes of Health (U.S.) (Grant GM117370), Swedish Research Council (Postdoctoral Fellowship VR 2017-00372), Damon Runyon Cancer Research Foundation ( Fellowship 2309-17)

Published
2020

28. Abstract GS3-10: Partitioning of cancer therapeutics in nuclear condensates

Author

Klein, Isaac, primary, Boija, Ann, additional, Afeyan, Lena, additional, Hawken, Susana Wilson, additional, Fan, Mengyang, additional, Dall'Agnese, Alessandra, additional, Oksuz, Ozgur, additional, Henninger, Jonathan, additional, Shrinivas, Krishna, additional, Sabari, Benjamin, additional, Sagi, Ido, additional, Clark, Victoria, additional, Platt, Jesse, additional, Kar, Mrityunjoy, additional, McCall, Patrick, additional, Zamudio, Alicia, additional, Mantiega, John, additional, Coffey, Eliot, additional, Li, Charles, additional, Hannett, Nancy, additional, Guo, Yang, additional, Decker, Tim-Michael, additional, Lee, Tong, additional, Zhang, Tinghu, additional, Weng, Jing-Ke, additional, Taatjes, Dylan, additional, Chakraborty, Arup, additional, Sharp, Phillip, additional, Chang, Young Tae, additional, Hyman, Anthony, additional, Gray, Nathanael, additional, and Young, Richard, additional

Published
2021
Full Text
View/download PDF

32. Abstract PO-063: Impact of cancer history on outcomes among hospitalized COVID-19 patients: A case-control analysis

Author

Klein, Isaac, primary, Rosenberg, Shoshana, additional, Kotton, Camille, additional, Reynolds, Kerry, additional, Zubiri, Leyre, additional, Gaither, Rachel, additional, Freeman, Hannah, additional, Kirkner, Greg, additional, Rhee, Chanu, additional, Klompas, Michael, additional, Baker, Meghan, additional, Wadleigh, Martha, additional, Winer, Eric, additional, and Partridge, Ann, additional

Published
2020
Full Text
View/download PDF

33. Partitioning of cancer therapeutics in nuclear condensates

Author

Klein, Isaac A., primary, Boija, Ann, additional, Afeyan, Lena K., additional, Hawken, Susana Wilson, additional, Fan, Mengyang, additional, Dall'Agnese, Alessandra, additional, Oksuz, Ozgur, additional, Henninger, Jonathan E., additional, Shrinivas, Krishna, additional, Sabari, Benjamin R., additional, Sagi, Ido, additional, Clark, Victoria E., additional, Platt, Jesse M., additional, Kar, Mrityunjoy, additional, McCall, Patrick M., additional, Zamudio, Alicia V., additional, Manteiga, John C., additional, Coffey, Eliot L., additional, Li, Charles H., additional, Hannett, Nancy M., additional, Guo, Yang Eric, additional, Decker, Tim-Michael, additional, Lee, Tong Ihn, additional, Zhang, Tinghu, additional, Weng, Jing-Ke, additional, Taatjes, Dylan J., additional, Chakraborty, Arup, additional, Sharp, Phillip A., additional, Chang, Young Tae, additional, Hyman, Anthony A., additional, Gray, Nathanael S., additional, and Young, Richard A., additional

Published
2020
Full Text
View/download PDF

34. Mediator Condensates Localize Signaling Factors to Key Cell Identity Genes

Author

Zamudio, Alicia V., primary, Dall’Agnese, Alessandra, additional, Henninger, Jonathan E., additional, Manteiga, John C., additional, Afeyan, Lena K., additional, Hannett, Nancy M., additional, Coffey, Eliot L., additional, Li, Charles H., additional, Oksuz, Ozgur, additional, Sabari, Benjamin R., additional, Boija, Ann, additional, Klein, Isaac A., additional, Hawken, Susana W., additional, Spille, Jan-Hendrik, additional, Decker, Tim-Michael, additional, Cisse, Ibrahim I., additional, Abraham, Brian J., additional, Lee, Tong I., additional, Taatjes, Dylan J., additional, Schuijers, Jurian, additional, and Young, Richard A., additional

Published
2019
Full Text
View/download PDF

35. Coactivator condensation at super-enhancers links phase separation and gene control

Author

Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Chemistry, Massachusetts Institute of Technology. Department of Physics, Koch Institute for Integrative Cancer Research at MIT, Coffey, Eliot Leo, Shrinivas, Krishna, Zamudio Montes de Oca, Alicia, Manteiga, John Colonnese, Li, Charles Han, Vasile, Eliza, Cisse, Ibrahim I, Sharp, Phillip A, Chakraborty, Arup K, Young, Richard A, Sabari, Benjamin R., Dall’Agnese, Alessandra, Boija, Ann, Klein, Isaac A., Abraham, Brian J., Hannett, Nancy M., Guo, Yang E., Day, Daniel S., Schuijers, Jurian, Hnisz, Denes, Lee, Tong Ihn, Sharp, Phillip A., Young, Richard A., Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Biology, Massachusetts Institute of Technology. Department of Chemical Engineering, Massachusetts Institute of Technology. Department of Chemistry, Massachusetts Institute of Technology. Department of Physics, Koch Institute for Integrative Cancer Research at MIT, Coffey, Eliot Leo, Shrinivas, Krishna, Zamudio Montes de Oca, Alicia, Manteiga, John Colonnese, Li, Charles Han, Vasile, Eliza, Cisse, Ibrahim I, Sharp, Phillip A, Chakraborty, Arup K, Young, Richard A, Sabari, Benjamin R., Dall’Agnese, Alessandra, Boija, Ann, Klein, Isaac A., Abraham, Brian J., Hannett, Nancy M., Guo, Yang E., Day, Daniel S., Schuijers, Jurian, Hnisz, Denes, Lee, Tong Ihn, Sharp, Phillip A., and Young, Richard A.

Abstract

Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of the transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets, and MED1-IDR droplets can compartmentalize and concentrate the transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in the control of key cell-identity genes., National Institutes of Health (U.S.) (Grant GM123511), National Institutes of Health (U.S.) (Grant P01-CA042063), National Science Foundation (U.S.) (Grant PHY-1743900), National Cancer Institute (U.S.) (Grant P30-CA14051)

Published
2019

36. Predicting master transcription factors from pan-cancer expression data

Author

Reddy, Jessica, primary, Fonseca, Marcos A. S., additional, Corona, Rosario I, additional, Nameki, Robbin, additional, Segato Dezem, Felipe, additional, Klein, Isaac A., additional, Chang, Heidi, additional, Chaves-Moreira, Daniele, additional, Afeyan, Lena, additional, Malta, Tathiane M, additional, Lin, Xianzhi, additional, Abbasi, Forough, additional, Font-Tello, Alba, additional, Sabedot, Thais, additional, Cejas, Paloma, additional, Rodríguez-Malavé, Norma, additional, Seo, Ji-Heui, additional, Lin, De-Chen, additional, Matulonis, Ursula, additional, Karlan, Beth Y, additional, Gayther, Simon A, additional, Gusev, Alexander, additional, Noushmehr, Houtan, additional, Long, Henry, additional, Freedman, Matthew L., additional, Drapkin, Ronny, additional, Abraham, Brian J, additional, Young, Richard A., additional, and Lawrenson, Kate, additional

Published
2019
Full Text
View/download PDF

37. Enhancer Features that Drive Formation of Transcriptional Condensates

Author

Shrinivas, Krishna, primary, Sabari, Benjamin R., additional, Coffey, Eliot L., additional, Klein, Isaac A., additional, Boija, Ann, additional, Zamudio, Alicia V., additional, Schuijers, Jurian, additional, Hannett, Nancy M., additional, Sharp, Phillip A., additional, Young, Richard A., additional, and Chakraborty, Arup K., additional

Published
2019
Full Text
View/download PDF

38. Abstract 2615: Systematic approaches to predict oncogenic transcriptional regulatory circuitries identify important nodes in high-grade serous ovarian cancer

Author

Abraham, Brian J., primary, Reddy, Jessica, additional, Fonseca, Marcos A., additional, Klein, Isaac A., additional, Afeyan, Lena K., additional, Corona, Rosario I., additional, Cejas, Paloma, additional, Segato, Felipe, additional, Karlan, Beth Y., additional, Gayther, Simon A., additional, Freedman, Matthew L., additional, Noushmehr, Houtan, additional, Brown, Myles, additional, Matulonis, Ursula A., additional, Lawrenson, Kate, additional, and Young, Richard A., additional

Published
2019
Full Text
View/download PDF

39. lncRNADIGITand BRD3 protein form phase-separated condensates to regulate endoderm differentiation

Author

Daneshvar, Kaveh, primary, Ardehali, M. Behfar, additional, Klein, Isaac A., additional, Kratkiewicz, Arcadia J., additional, Zhou, Chan, additional, Mahpour, Amin, additional, Cook, Brett M., additional, Li, Wenyang, additional, Pondick, Joshua V., additional, Moran, Sean P., additional, Young, Richard A., additional, Kingston, Robert E., additional, and Mullen, Alan C., additional

Published
2019
Full Text
View/download PDF

40. Enhancer features that drive formation of transcriptional condensates

Author

Shrinivas, Krishna, primary, Sabari, Benjamin R., additional, Coffey, Eliot L., additional, Klein, Isaac A., additional, Boija, Ann, additional, Zamudio, Alicia V., additional, Schuijers, Jurian, additional, Hannett, Nancy M., additional, Sharp, Phillip A., additional, Young, Richard A., additional, and Chakraborty, Arup K., additional

Published
2018
Full Text
View/download PDF

41. Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

Author

Boija, Ann, primary, Klein, Isaac A., additional, Sabari, Benjamin R., additional, Dall’Agnese, Alessandra, additional, Coffey, Eliot L., additional, Zamudio, Alicia V., additional, Li, Charles H., additional, Shrinivas, Krishna, additional, Manteiga, John C., additional, Hannett, Nancy M., additional, Abraham, Brian J., additional, Afeyan, Lena K., additional, Guo, Yang E., additional, Rimel, Jenna K., additional, Fant, Charli B., additional, Schuijers, Jurian, additional, Lee, Tong Ihn, additional, Taatjes, Dylan J., additional, and Young, Richard A., additional

Published
2018
Full Text
View/download PDF

46. Translocation-Capture Sequencing Reveals the Extent and Nature of Chromosomal Rearrangements in B Lymphocytes

Author

Klein, Isaac A., primary, Resch, Wolfgang, additional, Jankovic, Mila, additional, Oliveira, Thiago, additional, Yamane, Arito, additional, Nakahashi, Hirotaka, additional, Di Virgilio, Michela, additional, Bothmer, Anne, additional, Nussenzweig, Andre, additional, Robbiani, Davide F., additional, Casellas, Rafael, additional, and Nussenzweig, Michel C., additional

Published
2011
Full Text
View/download PDF

47. Regulation of DNA End Joining, Resection, and Immunoglobulin Class Switch Recombination by 53BP1

Author

Bothmer, Anne, primary, Robbiani, Davide F., additional, Di Virgilio, Michela, additional, Bunting, Samuel F., additional, Klein, Isaac A., additional, Feldhahn, Niklas, additional, Barlow, Jacqueline, additional, Chen, Hua-Tang, additional, Bosque, David, additional, Callen, Elsa, additional, Nussenzweig, André, additional, and Nussenzweig, Michel C., additional

Published
2011
Full Text
View/download PDF

48. Activation-Induced Cytidine Deaminase Targets DNA at Sites of RNA Polymerase II Stalling by Interaction with Spt5

Author

Pavri, Rushad, primary, Gazumyan, Anna, additional, Jankovic, Mila, additional, Di Virgilio, Michela, additional, Klein, Isaac, additional, Ansarah-Sobrinho, Camilo, additional, Resch, Wolfgang, additional, Yamane, Arito, additional, San-Martin, Bernardo Reina, additional, Barreto, Vasco, additional, Nieland, Thomas J., additional, Root, David E., additional, Casellas, Rafael, additional, and Nussenzweig, Michel C., additional

Published
2010
Full Text
View/download PDF

49. Class switching and meiotic defects in mice lacking the E3 ubiquitin ligase RNF8

Author

Santos, Margarida Almeida, primary, Huen, Michael S.Y., additional, Jankovic, Mila, additional, Chen, Hua-Tang, additional, López-Contreras, Andrés J., additional, Klein, Isaac A., additional, Wong, Nancy, additional, Barbancho, Juan L.R., additional, Fernandez-Capetillo, Oscar, additional, Nussenzweig, Michel C., additional, Chen, Junjie, additional, and Nussenzweig, André, additional

Published
2010
Full Text
View/download PDF

50. AID Produces DNA Double-Strand Breaks in Non-Ig Genes and Mature B Cell Lymphomas with Reciprocal Chromosome Translocations

Author

Robbiani, Davide F., primary, Bunting, Samuel, additional, Feldhahn, Niklas, additional, Bothmer, Anne, additional, Camps, Jordi, additional, Deroubaix, Stephanie, additional, McBride, Kevin M., additional, Klein, Isaac A., additional, Stone, Gary, additional, Eisenreich, Thomas R., additional, Ried, Thomas, additional, Nussenzweig, André, additional, and Nussenzweig, Michel C., additional

Published
2009
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results