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3. Loss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment

Author

Li, Jie, Chin, Christopher R., Ying, Hsia-Yuan, Meydan, Cem, Teater, Matthew R., Xia, Min, Farinha, Pedro, Takata, Katsuyoshi, Chu, Chi-Shuen, Jiang, Yiyue, Eagles, Jenna, Passerini, Verena, Tang, Zhanyun, Rivas, Martin A., Weigert, Oliver, Pugh, Trevor J., Chadburn, Amy, Steidl, Christian, Scott, David W., Roeder, Robert G., Mason, Christopher E., Zappasodi, Roberta, Béguelin, Wendy, and Melnick, Ari M.

Published
2024
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7. MLL-AF4 cooperates with PAF1 and FACT to drive high-density enhancer interactions in leukemia

Author

Crump, Nicholas T., Smith, Alastair L., Godfrey, Laura, Dopico-Fernandez, Ana M., Denny, Nicholas, Harman, Joe R., Hamley, Joseph C., Jackson, Nicole E., Chahrour, Catherine, Riva, Simone, Rice, Siobhan, Kim, Jaehoon, Basrur, Venkatesha, Fermin, Damian, Elenitoba-Johnson, Kojo, Roeder, Robert G., Allis, C. David, Roberts, Irene, Roy, Anindita, Geng, Huimin, Davies, James O. J., and Milne, Thomas A.

Published
2023
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11. Histone H3 lysine 27 crotonylation mediates gene transcriptional repression in chromatin

Author

Liu, Nan, Konuma, Tsuyoshi, Sharma, Rajal, Wang, Deyu, Zhao, Nan, Cao, Lingling, Ju, Ying, Liu, Di, Wang, Shuai, Bosch, Almudena, Sun, Yifei, Zhang, Siwei, Ji, Donglei, Nagatoishi, Satoru, Suzuki, Noa, Kikuchi, Masaki, Wakamori, Masatoshi, Zhao, Chengcheng, Ren, Chunyan, Zhou, Thomas Jiachi, Xu, Yaoyao, Meslamani, Jamel, Fu, Shibo, Umehara, Takashi, Tsumoto, Kouhei, Akashi, Satoko, Zeng, Lei, Roeder, Robert G., Walsh, Martin J., Zhang, Qiang, and Zhou, Ming-Ming

Published
2023
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13. The Histone Deacetylase SIRT6 Restrains Transcription Elongation via Promoter-Proximal Pausing.

Author

Etchegaray, Jean-Pierre, Zhong, Lei, Li, Catherine, Henriques, Telmo, Ablondi, Eileen, Nakadai, Tomoyoshi, Van Rechem, Capucine, Ferrer, Christina, Ross, Kenneth N, Choi, Jee-Eun, Samarakkody, Ann, Ji, Fei, Chang, Andrew, Sadreyev, Ruslan I, Ramaswamy, Sridhar, Nechaev, Sergei, Whetstine, Johnathan R, Roeder, Robert G, Adelman, Karen, Goren, Alon, and Mostoslavsky, Raul

Subjects
Cell Line, Humans, Sirtuins, RNA Polymerase II, Cell Cycle Proteins, Proto-Oncogene Proteins c-myc, Histones, Transcription Factors, Transcriptional Elongation Factors, Gene Deletion, Acetylation, Promoter Regions, Genetic, Transcription Elongation, Genetic, BRD4, NELF, SIRT6, chromatin, epigenetics, histone deacetylation, transcription elongation, transcriptional pausing, Promoter Regions, Genetic, Transcription Elongation, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Transcriptional regulation in eukaryotes occurs at promoter-proximal regions wherein transcriptionally engaged RNA polymerase II (Pol II) pauses before proceeding toward productive elongation. The role of chromatin in pausing remains poorly understood. Here, we demonstrate that the histone deacetylase SIRT6 binds to Pol II and prevents the release of the negative elongation factor (NELF), thus stabilizing Pol II promoter-proximal pausing. Genetic depletion of SIRT6 or its chromatin deficiency upon glucose deprivation causes intragenic enrichment of acetylated histone H3 at lysines 9 (H3K9ac) and 56 (H3K56ac), activation of cyclin-dependent kinase 9 (CDK9)-that phosphorylates NELF and the carboxyl terminal domain of Pol II-and enrichment of the positive transcription elongation factors MYC, BRD4, PAF1, and the super elongation factors AFF4 and ELL2. These events lead to increased expression of genes involved in metabolism, protein synthesis, and embryonic development. Our results identified SIRT6 as a Pol II promoter-proximal pausing-dedicated histone deacetylase.

Published
2019

18. Architecture of Pol II(G) and molecular mechanism of transcription regulation by Gdown1

Author

Jishage, Miki, Yu, Xiaodi, Shi, Yi, Ganesan, Sai J, Chen, Wei-Yi, Sali, Andrej, Chait, Brian T, Asturias, Francisco J, and Roeder, Robert G

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Binding Sites, Cryoelectron Microscopy, Drosophila melanogaster, Gene Expression Regulation, HeLa Cells, Humans, RNA Polymerase II, Transcription Factors, TFII, Transcription, Genetic, Hela Cells, Chemical Sciences, Medical and Health Sciences, Biophysics, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Chemical sciences
Abstract

Tight binding of Gdown1 represses RNA polymerase II (Pol II) function in a manner that is reversed by Mediator, but the structural basis of these processes is unclear. Although Gdown1 is intrinsically disordered, its Pol II interacting domains were localized and shown to occlude transcription factor IIF (TFIIF) and transcription factor IIB (TFIIB) binding by perfect positioning on their Pol II interaction sites. Robust binding of Gdown1 to Pol II is established by cooperative interactions of a strong Pol II binding region and two weaker binding modulatory regions, thus providing a mechanism both for tight Pol II binding and transcription inhibition and for its reversal. In support of a physiological function for Gdown1 in transcription repression, Gdown1 co-localizes with Pol II in transcriptionally silent nuclei of early Drosophila embryos but re-localizes to the cytoplasm during zygotic genome activation. Our study reveals a self-inactivation through Gdown1 binding as a unique mode of repression in Pol II function.

Published
2018

22. CREBBP Inactivation Promotes the Development of HDAC3-Dependent Lymphomas

Author

Jiang, Yanwen, Ortega-Molina, Ana, Geng, Huimin, Ying, Hsia-Yuan, Hatzi, Katerina, Parsa, Sara, McNally, Dylan, Wang, Ling, Doane, Ashley S, Agirre, Xabier, Teater, Matt, Meydan, Cem, Li, Zhuoning, Poloway, David, Wang, Shenqiu, Ennishi, Daisuke, Scott, David W, Stengel, Kristy R, Kranz, Janice E, Holson, Edward, Sharma, Sneh, Young, James W, Chu, Chi-Shuen, Roeder, Robert G, Shaknovich, Rita, Hiebert, Scott W, Gascoyne, Randy D, Tam, Wayne, Elemento, Olivier, Wendel, Hans-Guido, and Melnick, Ari M

Subjects
Hematology, Rare Diseases, Lymphoma, Genetics, Clinical Research, Cancer, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Acetylation, Animals, CREB-Binding Protein, Cell Line, Tumor, Enhancer Elements, Genetic, Gene Knockout Techniques, Germinal Center, Histone Deacetylases, Histones, Humans, Lymphoma, Large B-Cell, Diffuse, Mice, Mutation, Neoplasm Transplantation, Nuclear Receptor Co-Repressor 2, Proto-Oncogene Proteins c-bcl-6, Transcription, Genetic, Oncology and Carcinogenesis
Abstract

Somatic mutations in CREBBP occur frequently in B-cell lymphoma. Here, we show that loss of CREBBP facilitates the development of germinal center (GC)-derived lymphomas in mice. In both human and murine lymphomas, CREBBP loss-of-function resulted in focal depletion of enhancer H3K27 acetylation and aberrant transcriptional silencing of genes that regulate B-cell signaling and immune responses, including class II MHC. Mechanistically, CREBBP-regulated enhancers are counter-regulated by the BCL6 transcriptional repressor in a complex with SMRT and HDAC3, which we found to bind extensively to MHC class II loci. HDAC3 loss-of-function rescued repression of these enhancers and corresponding genes, including MHC class II, and more profoundly suppressed CREBBP-mutant lymphomas in vitro and in vivo Hence, CREBBP loss-of-function contributes to lymphomagenesis by enabling unopposed suppression of enhancers by BCL6/SMRT/HDAC3 complexes, suggesting HDAC3-targeted therapy as a precision approach for CREBBP-mutant lymphomas.SignificanceOur findings establish the tumor suppressor function of CREBBP in GC lymphomas in which CREBBP mutations disable acetylation and result in unopposed deacetylation by BCL6/SMRT/HDAC3 complexes at enhancers of B-cell signaling and immune response genes. Hence, inhibition of HDAC3 can restore the enhancer histone acetylation and may serve as a targeted therapy for CREBBP-mutant lymphomas. Cancer Discov; 7(1); 38-53. ©2016 AACR.See related commentary by Höpken, p. 14This article is highlighted in the In This Issue feature, p. 1.

Published
2017

28. Chromatin Kinases Act on Transcription Factors and Histone Tails in Regulation of Inducible Transcription

Author

Josefowicz, Steven Z, Shimada, Miho, Armache, Anja, Li, Charles H, Miller, Rand M, Lin, Shu, Yang, Aerin, Dill, Brian D, Molina, Henrik, Park, Hee-Sung, Garcia, Benjamin A, Taunton, Jack, Roeder, Robert G, and Allis, C David

Subjects
Biochemistry and Cell Biology, Biological Sciences, Genetics, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, 2.1 Biological and endogenous factors, Bacterial Proteins, Cell Cycle Proteins, Cell Line, Tumor, Chromatin, Epithelial Cells, Feedback, Physiological, HeLa Cells, Histones, Humans, Kinetics, Luminescent Proteins, Mitosis, Models, Statistical, Molecular Imaging, Recombinant Fusion Proteins, Time Factors, Transcription Factors, Transcription, Genetic, Hela Cells, H3S28ph, chromatin, epigenetics, histone phosphorylation, inflammation, macrophage, mitogen- and stress-activated protein kinase, p300, transcription, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

The inflammatory response requires coordinated activation of both transcription factors and chromatin to induce transcription for defense against pathogens and environmental insults. We sought to elucidate the connections between inflammatory signaling pathways and chromatin through genomic footprinting of kinase activity and unbiased identification of prominent histone phosphorylation events. We identified H3 serine 28 phosphorylation (H3S28ph) as the principal stimulation-dependent histone modification and observed its enrichment at induced genes in mouse macrophages stimulated with bacterial lipopolysaccharide. Using pharmacological and genetic approaches, we identified mitogen- and stress-activated protein kinases (MSKs) as primary mediators of H3S28ph in macrophages. Cell-free transcription assays demonstrated that H3S28ph directly promotes p300/CBP-dependent transcription. Further, MSKs can activate both signal-responsive transcription factors and the chromatin template with additive effects on transcription. Specific inhibition of MSKs in macrophages selectively reduced transcription of stimulation-induced genes. Our results suggest that MSKs incorporate upstream signaling inputs and control multiple downstream regulators of inducible transcription.

Published
2016

30. Different roles of E proteins in t(8;21) leukemia : E2-2 compromises the function of AETFC and negatively regulates leukemogenesis

Author

Liu, Na, Song, Junhong, Xie, Yangyang, Wang, Xiao-Lin, Rong, Bowen, Man, Na, Zhang, Meng-Meng, Zhang, Qunling, Gao, Fei-Fei, Du, Mei-Rong, Zhang, Ying, Shen, Jian, Xu, Chun-Hui, Hu, Cheng-Long, Wu, Ji-Chuan, Liu, Ping, Zhang, Yuan-Liang, Xie, Yin-Yin, Liu, Ping, Huang, Jin-Yan, Huang, Qiu-Hua, Lan, Fei, Shen, Shuhong, Nimer, Stephen D., Chen, Zhu, Chen, Sai-Juan, Roeder, Robert G., Wang, Lan, and Sun, Xiao-Jian

Published
2019

31. Self-Enforcing Feedback Activation between BCL6 and Pre-B Cell Receptor Signaling Defines a Distinct Subtype of Acute Lymphoblastic Leukemia

Author

Geng, Huimin, Hurtz, Christian, Lenz, Kyle B, Chen, Zhengshan, Baumjohann, Dirk, Thompson, Sarah, Goloviznina, Natalya A, Chen, Wei-Yi, Huan, Jianya, LaTocha, Dorian, Ballabio, Erica, Xiao, Gang, Lee, Jae-Woong, Deucher, Anne, Qi, Zhongxia, Park, Eugene, Huang, Chuanxin, Nahar, Rahul, Kweon, Soo-Mi, Shojaee, Seyedmehdi, Chan, Lai N, Yu, Jingwei, Kornblau, Steven M, Bijl, Janetta J, Ye, B Hilda, Ansel, K Mark, Paietta, Elisabeth, Melnick, Ari, Hunger, Stephen P, Kurre, Peter, Tyner, Jeffrey W, Loh, Mignon L, Roeder, Robert G, Druker, Brian J, Burger, Jan A, Milne, Thomas A, Chang, Bill H, and Müschen, Markus

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Rare Diseases, Pediatric, Childhood Leukemia, Vaccine Related, Cancer, Hematology, Pediatric Cancer, Basic Helix-Loop-Helix Transcription Factors, Clinical Trials as Topic, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Molecular Sequence Data, Phosphatidylinositol 3-Kinase, Pre-B-Cell Leukemia Transcription Factor 1, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Precursor Cells, B-Lymphoid, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-6, Signal Transduction, Syk Kinase, Up-Regulation, src-Family Kinases, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR(+) ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. In vivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR(+) ALL.

Published
2015

36. Loss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment.

Author

Jie Li, Chin, Christopher R., Hsia-Yuan Ying, Meydan, Cem, Teater, Matthew R., MinXia, Farinha, Pedro, Takata, Katsuyoshi, Chi-Shuen Chu, Yiyue Jiang, Eagles, Jenna, Passerini, Verena, Zhanyun Tang, Rivas, Martin A., Weigert, Oliver, Pugh, Trevor J., Chadburn, Amy, Steidl, Christian, Scott, David W., and Roeder, Robert G.

Abstract

Despite regulating overlapping gene enhancers and pathways, CREBBP and KMT2D mutations recurrently co-occur in germinal center (GC) B cell-derived lymphomas, suggesting potential oncogenic cooperation. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d induces a more severe mouse lymphoma phenotype (vs either allele alone) and unexpectedly confers an immune evasive microenvironment manifesting as CD8+ T-cell exhaustion and reduced infiltration. This is linked to profound repression of immune synapse genes that mediate crosstalk with T-cells, resulting in aberrant GC B cell fate decisions. From the epigenetic perspective, we observe interaction and mutually dependent binding and function of CREBBP and KMT2D on chromatin. Their combined deficiency preferentially impairs activation of immune synapse-responsive super-enhancers, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Together, our data provide an example where chromatin modifier mutations cooperatively shape and induce an immune-evasive microenvironment to facilitate lymphomagenesis. [ABSTRACT FROM AUTHOR]

Published
2024
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38. 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

41. H3K4me3 Interactions with TAF3 Regulate Preinitiation Complex Assembly and Selective Gene Activation

Author

Lauberth, Shannon M, Nakayama, Takahiro, Wu, Xiaolin, Ferris, Andrea L, Tang, Zhanyun, Hughes, Stephen H, and Roeder, Robert G

Subjects
Biochemistry and Cell Biology, Biological Sciences, Biotechnology, Genetics, 2.1 Biological and endogenous factors, Aetiology, Cell Line, Tumor, Histone Code, Histones, Humans, Lysine, Methylation, TATA Box, TATA-Binding Protein Associated Factors, Transcription Factor TFIID, Transcription Initiation, Genetic, Transcriptional Activation, Tumor Suppressor Protein p53, p300-CBP Transcription Factors, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

Histone modifications regulate chromatin-dependent processes, yet the mechanisms by which they contribute to specific outcomes remain unclear. H3K4me3 is a prominent histone mark that is associated with active genes and promotes transcription through interactions with effector proteins that include initiation factor TFIID. We demonstrate that H3K4me3-TAF3 interactions direct global TFIID recruitment to active genes, some of which are p53 targets. Further analyses show that (1) H3K4me3 enhances p53-dependent transcription by stimulating preinitiation complex (PIC) formation; (2) H3K4me3, through TAF3 interactions, can act either independently or cooperatively with the TATA box to direct PIC formation and transcription; and (3) H3K4me3-TAF3/TFIID interactions regulate gene-selective functions of p53 in response to genotoxic stress. Our findings indicate a mechanism by which H3K4me3 directs PIC assembly for the rapid induction of specific p53 target genes.

Published
2013

42. Metabolic regulation of gene expression by histone lactylation

Author

Zhang, Di, Tang, Zhanyun, Huang, He, Zhou, Guolin, Cui, Chang, Weng, Yejing, Liu, Wenchao, Kim, Sunjoo, Lee, Sangkyu, Perez-Neut, Mathew, Ding, Jun, Czyz, Daniel, Hu, Rong, Ye, Zhen, He, Maomao, Zheng, Y. George, Shuman, Howard A., Dai, Lunzhi, Ren, Bing, Roeder, Robert G., Becker, Lev, and Zhao, Yingming

Published
2019
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45. Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3

Author

Farrelly, Lorna A., Thompson, Robert E., Zhao, Shuai, Lepack, Ashley E., Lyu, Yang, Bhanu, Natarajan V., Zhang, Baichao, Loh, Yong-Hwee E., Ramakrishnan, Aarthi, Vadodaria, Krishna C., Heard, Kelly J., Erikson, Galina, Nakadai, Tomoyoshi, Bastle, Ryan M., Lukasak, Bradley J., Zebroski, III, Henry, Alenina, Natalia, Bader, Michael, Berton, Olivier, Roeder, Robert G., Molina, Henrik, Gage, Fred H., Shen, Li, Garcia, Benjamin A., Li, Haitao, Muir, Tom W., and Maze, Ian

Published
2019
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