scholarly journals Mammalian SWI/SNF collaborates with a polycomb-associated protein to regulate male germ line transcription in the mouse

2018 ◽  
Author(s):  
Debashish U. Menon ◽  
Yoichiro Shibata ◽  
Weipeng Mu ◽  
Terry Magnuson
Keyword(s):  
Chromatin Remodeling ◽  
Germ Line ◽  
Chromatin Accessibility ◽  
Catalytic Subunit ◽  
Histone H2a ◽  
Meiotic Progression ◽  
Chromatin Remodeling Complex ◽  
Epigenetic Modifiers ◽  
Summary Statement ◽  
Target Promoters

AbstractA deficiency in BRG1, the catalytic subunit of the SWI/SNF chromatin remodeling complex, results in a meiotic arrest during spermatogenesis. Here, we explore the causative mechanisms. BRG1 is preferentially enriched at active promoters of genes essential for spermatogonial pluripotency and meiosis. In contrast, BRG1 is also associated with the repression of somatic genes. Chromatin accessibility at these target promoters is dependent upon BRG1. These results favor a model where BRG1 coordinates spermatogenic transcription to ensure meiotic progression. In spermatocytes, BRG1 interacts with SCML2, a testes specific PRC1 factor that is associated with the repression of somatic genes. We present evidence to suggest that BRG1 and SCML2 concordantly regulate genes during meiosis. Furthermore, BRG1 is required for the proper localization of SCML2 and its associated deubiquitinase, USP7, to the sex chromosomes during pachynema. SCML2 associated, mono ubiquitination of histone H2A lysine 119 (H2AK119ub1) and acetylation of histone lysine 27 (H3K27ac) are elevated in Brg1cKO testes. Coincidentally, the PRC1 ubiquitin ligase, RNF2 is activated while a histone H2A/H2B deubiquitinase, USP3 is repressed. Thus, BRG1 impacts the male epigenome by influencing the localization and expression of epigenetic modifiers. This mechanism highlights a novel paradigm of co-operativity between SWI/SNF and PRC1.Summary statementBRG1, a catalytic subunit of SWI/SNF chromatin remodeling complex, interacts with SCML2 (Sex comb on midleg-like 2), a polycomb repressive 1 (PRC1) factor, to regulate transcription during spermatogenesis. This represents a novel paradigm of SWI/SNF-PRC1 co-operation during gametogenesis.

Abstract 14745: The Histone Reader PHF7 Cooperates With the SWI/SNF Complex at Cardiac Super Enhancers to Promote Direct Cardiac Reprogramming

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Glynnis A Garry ◽  
Svetlana Bezprozvannaya ◽  
Kenian Chen ◽  
Huanyu Zhou ◽  
Hisayuki Hashimoto ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Chromatin Remodeling ◽  
Therapeutic Strategy ◽  
Chromatin Accessibility ◽  
Epigenetic Factor ◽  
Epigenetic Modifiers ◽  
Regulatory Circuit ◽  
Gene Regulatory ◽  
Cardiac Transcription Factors ◽  
Adult Fibroblasts

Direct cardiac reprogramming of fibroblasts to cardiomyocytes presents an attractive therapeutic strategy to restore cardiac function following injury. Cardiac reprogramming was initially achieved through the overexpression of the transcription factors Gata4, Mef2c, and Tbx5 (GMT), and later, Hand2 (GHMT) and Akt1 (AGHMT) were found to further enhance this process. Yet, staunch epigenetic barriers severely limit the ability of these cocktails to reprogram adult fibroblasts. We undertook a screen of mammalian gene regulatory factors to discover novel regulators of cardiac reprogramming in adult fibroblasts and identified the histone reader PHF7 as the most potent activating factor. Mechanistically, PHF7 localizes to cardiac super enhancers in fibroblasts, and through cooperation with the SWI/SNF complex, increases chromatin accessibility and transcription factor binding at these sites. Further, PHF7 recruits cardiac transcription factors to activate a core regulatory circuit in reprogramming. Importantly, PHF7 is the first epigenetic factor shown to achieve efficient reprogramming in the absence of Gata4. Here, we highlight the underexplored necessity of cardiac epigenetic modifiers, such as PHF7, in harnessing chromatin remodeling and transcriptional complexes to overcome critical barriers to direct cardiac reprogramming.

scholarly journals ATPase SRCAP is a new player in cell division, uncovering molecular aspects of Floating-Harbor syndrome

2020 ◽  
Author(s):  
Giovanni Messina ◽  
Yuri Prozzillo ◽  
Francesca Delle Monache ◽  
Maria Virginia Santopietro ◽  
Maria Teresa Atterrato ◽  
...  
Keyword(s):  
Cell Division ◽  
Chromatin Remodeling ◽  
Catalytic Subunit ◽  
Current View ◽  
Mitotic Apparatus ◽  
Direct Role ◽  
The Core ◽  
Chromatin Remodeling Complex ◽  
Evolutionarily Conserved ◽  
Floating Harbor Syndrome

AbstractFloating-Harbor syndrome (FHS) is a rare genetic disease affecting human development caused by heterozygous truncating mutations in the Srcap gene, which encodes the ATPase SRCAP, the core catalytic subunit of the homonymous chromatin-remodeling complex. Using a combined approach, we studied the involvement of SRCAP protein in cell cycle progression in HeLa cells. In addition to the canonical localization in interphase nuclei, both SRCAP and its Drosophila orthologue DOMINO-A localized to the mitotic apparatus after nuclear envelope breakdown. Moreover, SRCAP and DOMINO-A depletion impaired mitosis and cytokinesis in human and Drosophila cells, respectively. Importantly, SRCAP interacted with several cytokinesis regulators at telophase, strongly supporting a direct role in cytokinesis, independent of its chromatin remodeling functions. Our results provide clues about previously undetected, evolutionarily conserved roles of SRCAP in ensuring proper mitosis and cytokinesis. We propose that perturbations in cell division contribute to the onset of developmental defects characteristic of FHS.SummarySignificance statementSrcap is the causative gene of the rare Floating Harbor syndrome (FHS). It encodes the ATPase SRCAP, the core catalytic subunit of the homonymous multiprotein chromatin-remodeling complex in humans, which promotes the exchange of canonical histone H2A with the H2A.Z variant. According to the current view on SRCAP protein functions, FHS is caused by chromatin remodeling defects. Our findings suggest that, in addition to the established function as epigenetic regulator, SRCAP plays previously undetected and evolutionarily conserved roles in cell division. Hence, we propose that perturbations in cell division produced by SRCAP mutations are important causative factors co-occurring at the onset of FHS.

scholarly journals BAF chromatin remodeling complex subunit diversity promotes temporally distinct gene expression programs in cardiogenesis

2017 ◽  
Author(s):  
Swetansu K. Hota ◽  
Jeffrey R. Johnson ◽  
Erik Verschueren ◽  
Reuben Thomas ◽  
Aaron M. Blotnick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Chromatin Accessibility ◽  
Catalytic Subunit ◽  
Subunit Composition ◽  
Specific Gene ◽  
Cardiomyocyte Differentiation ◽  
Cardiac Progenitors ◽  
Baf Complex ◽  
Temporal Gene Expression

AbstractChromatin remodeling complexes instruct cellular differentiation and lineage specific transcription. The BRG1/BRM associated factor (BAF) complexes are important for several aspects of differentiation. We show that the catalytic subunit Brg1 has a specific role in cardiac precursors (CPs) to initiate cardiac gene expression programs and repress non-cardiac expression. Using immunoprecipitation with mass spectrometry (IP-MS), we determined the dynamic composition of BAF complexes during mammalian cardiac differentiation, and identified BAF60c (SMARCD3) and BAF170 (SMARCC2) as subunits enriched in CPs and cardiomyocytes (CM). Baf60c and Baf170 co-regulate gene expression with Brg1 in CPs, but in CMs control different gene expression programs, although still promoting a cardiac-specific gene set. BRG1, BAF60, and BAF170 all modulate chromatin accessibility, to either promote accessibility at activated genes, while closing up chromatin at repressed genes. BAF60c and BAF170 are required for proper BAF complex composition and stoichiometry, and promote BRG1 occupancy in CM. Additionally, BAF170 facilitates expulsion of BRG1-containing complexes in the transition from CP to CM. Thus, dynamic interdependent BAF complex subunit assembly modulates chromatin states and thereby directs temporal gene expression programs in cardiogenesis.Significance statementBRG1/BRM associated factors (BAF) form multi-subunit protein complexes that reorganize chromatin and regulate transcription. Specific BAF complex subunits have important roles during cell differentiation and development. We systematically identify BAF subunit composition and find temporal enrichment of subunits during cardiomyocyte differentiation. We find the catalytic subunit BRG1 has important contributions in initiating gene expression programs in cardiac progenitors along with cardiac-enriched subunits BAF60c and BAF170. Both these proteins regulated BAF subunit composition and chromatin accessibility and prevent expression of non-cardiac developmental genes during precursor to cardiomyocyte differentiation. Mechanistically, we find BAF170 destabilizes the BRG1 complex and expels BRG1 from cardiomyocyte-specific genes. Thus, our data shows synergies between diverse BAF subunits in facilitating temporal gene expression programs during cardiogenesis.

scholarly journals The High-Mobility-Group Box Protein SSRP1/T160 Is Essential for Cell Viability in Day 3.5 Mouse Embryos

2003 ◽  
Vol 23 (15) ◽  
pp. 5301-5307 ◽  
Author(s):  
Shang Cao ◽  
Heather Bendall ◽  
Geoffrey G. Hicks ◽  
Abudi Nashabi ◽  
Hitoshi Sakano ◽  
...  
Keyword(s):  
Cell Viability ◽  
Chromatin Remodeling ◽  
Germ Line ◽  
Embryonic Stem ◽  
High Mobility ◽  
High Mobility Group ◽  
Murine Embryonic Stem Cells ◽  
Chromatin Remodeling Complex ◽  
Independent Functions

ABSTRACT The high-mobility-group (HMG) SSRP1 protein is a member of a conserved chromatin-remodeling complex (FACT/DUF/CP) implicated in DNA replication, basal and regulated transcription, and DNA repair. To assist in the functional analysis of SSRP1, the Ssrp1 gene was targeted in murine embryonic stem cells, and the mutation was introduced into the germ line. Embryos homozygous for the targeted allele die soon after implantation, and preimplantation blastocysts are defective for cell outgrowth and/or survival in vitro. The Ssrp1 mutation was also crossed into a p53 null background without affecting growth and/or survival defects caused by loss of Ssrp1 function. Thus, Ssrp1 appears to encode nonredundant and p53-independent functions that are essential for cell viability.

Mechanistic and structural insights into histone H2A–H2B chaperone in chromatin regulation

2020 ◽  
Vol 477 (17) ◽  
pp. 3367-3386
Author(s):  
Yan Huang ◽  
Yaxin Dai ◽  
Zheng Zhou
Keyword(s):  
Chromatin Remodeling ◽  
Chromatin Structure ◽  
Current Knowledge ◽  
Histone Variants ◽  
Functional Study ◽  
Histone Chaperones ◽  
Chromatin Regulation ◽  
Histone H2a ◽  
Chromatin Remodeling Complex ◽  
Recent Advances

Histone chaperones include a wide variety of proteins which associate with histones and regulate chromatin structure. The classic H2A–H2B type of histone chaperones, and the chromatin remodeling complex components possessing H2A–H2B chaperone activity, show a broad range of structures and functions. Rapid progress in the structural and functional study of H2A–H2B chaperones extends our knowledge about the epigenetic regulation of chromatin. In this review, we summarize the most recent advances in the understanding of the structure and function of H2A–H2B chaperones that interact with either canonical or variant H2A–H2B dimers. We discuss the current knowledge of the H2A–H2B chaperones, which present no preference for canonical and variant H2A–H2B dimers, describing how they interact with H2A–H2B to fulfill their functions. We also review recent advances of H2A variant-specific chaperones, demarcating how they achieve specific recognition for histone variant H2A.Z and how these interactions regulate chromatin structure by nucleosome editing. We highlight the universal mechanism underlying H2A–H2B dimers recognition by a large variety of histone chaperones. These findings will shed insight into the biological impacts of histone chaperone, chromatin remodeling complex, and histone variants in chromatin regulation.

scholarly journals MUC1-C activates the PBAF chromatin remodeling complex in integrating redox balance with progression of human prostate cancer stem cells

Oncogene ◽  
2021 ◽  
Author(s):  
Masayuki Hagiwara ◽  
Atsushi Fushimi ◽  
Nami Yamashita ◽  
Atrayee Bhattacharya ◽  
Hasan Rajabi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Chromatin Remodeling ◽  
Target Genes ◽  
Redox Balance ◽  
Chromatin Accessibility ◽  
Pentose Phosphate ◽  
Antioxidant Genes ◽  
Chromatin Remodeling Complex ◽  
Prostate Cancer Stem Cells ◽  
Oncogenic Protein

AbstractThe polybromo-associated PBAF (SWI/SNF) chromatin remodeling complex, which includes PBRM1, ARID2, and BRD7, regulates cell differentiation and genomic integrity. MUC1-C is an oncogenic protein that drives lineage plasticity in prostate cancer (PC) progression. The present work demonstrates that MUC1-C induces PBRM1, ARID2, and BRD7 expression by the previously unrecognized E2F1-mediated activation of their respective promoters. The functional significance of the MUC1-C→PBAF pathway is supported by demonstrating involvement of MUC1-C in associating with nuclear PBAF and driving the NRF2 antioxidant gene transcriptome in PC cells. Mechanistically, MUC1-C forms a complex with NRF2 and PBRM1 on the NRF2 target SLC7A11 gene that encodes the xCT cystine-glutamate antiporter, increases chromatin accessibility and induces SLC7A11/xCT expression. We also show that MUC1-C and PBRM1 are necessary for induction of other NRF2 target genes, including G6PD and PGD that regulate the pentose phosphate pathway. Our results further demonstrate that MUC1-C integrates activation of PBRM1 with the regulation of antioxidant genes, ROS levels, pluripotency factor expression and the cancer stem cell (CSC) state. These findings reveal a role for MUC1-C in regulating PBAF, redox balance and lineage plasticity of PC CSC progression. Our findings also uncover involvement of MUC1-C in integrating the PBAF and BAF pathways in cancer.

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