Structure and Function of ATP-Dependent Chromatin Remodeling Complexes in Human Cancer

Dr. Cigall Kadoch will discuss how recent exome-and genome-wide sequencing studies in human cancers have unmasked a striking frequency of mutations in the genes encoding subunits of the mammalian SWI/SNF (mSWI/SNF) family of ATP-dependent chromatin remodeling complexes. Her laboratory uses biochemistry, structural biology, systems biology, and genomics-based approaches to define the mechanisms of chromatin and gene regulation carried out by the mSWI/SNF family of chromatin regulators. Specifically, they have studied rare, genetically well-defined pediatric cancers including synovial sarcoma, Ewing sarcoma, malignant rhabdoid tumor and others, all of which involve mSWI/SNF complex perturbations as critical drivers of their oncogenic programs. These studies have informed the diverse mechanisms underlying mSWI/SNF complex targeting and function in a wide array of cancers (including hematologic cancers) and developmental disorders and have provided new foundations for therapeutic development. Disclosures Kadoch: Foghorn Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Download Full-text

Mammalian SWI/SNF chromatin remodeling complexes and cancer: Mechanistic insights gained from human genomics

Science Advances ◽

10.1126/sciadv.1500447 ◽

2015 ◽

Vol 1 (5) ◽

pp. e1500447 ◽

Cited By ~ 336

Author(s):

Cigall Kadoch ◽

Gerald R. Crabtree

Keyword(s):

Chromatin Remodeling ◽

Human Cancer ◽

Human Genomics ◽

Chromatin Remodelers ◽

Fundamental Process ◽

Sequencing Studies ◽

Genes Encoding ◽

Chromatin Remodeling Complexes ◽

Tumor Types ◽

Oncogenic Function

Over the past 4 years, nearly 100 exome sequencing studies have revealed the high frequency of mutations in the genes encoding the subunits of ATP-dependent chromatin remodelers in human cancer. Most of these mutations are within the genes encoding subunits of the BAF (Brg/Brahma-associated factors) or mSWI/SNF complex, which is one of two dozen predicted ATP-dependent chromatin remodeling complexes in mammals. Considering BAF complexes as a single entity, the 15 subunits encoded by 29 genes are mutated in >20% of human cancer, across a broad range of tumor types. These observations demonstrate that there is little redundancy in the oncogenic function of BAF complexes with the other remodeling complexes, underscoring their unique roles. Several important conclusions emerge from these genomic data: specific subunits appear to be mutated in specific cancers, highlighting tissue-specific protective roles; mutations can function as tumor suppressors or oncogenes; mutations can be homozygous or, more commonly, heterozygous, implying their dosage-sensitive roles in an unknown yet fundamental process used to suppress the genesis of cancer. These new human genetic findings paired with biochemical studies are challenging old ideas on how chromatin remodeling complexes function, generating new hypotheses with respect to their normal and oncogenic mechanisms and highlighting potential avenues for therapeutic intervention in human cancer.

Download Full-text

The emerging role of ISWI chromatin remodeling complexes in cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02151-x ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Yanan Li ◽

Han Gong ◽

Pan Wang ◽

Yu Zhu ◽

Hongling Peng ◽

...

Keyword(s):

Tumor Progression ◽

Chromatin Remodeling ◽

Regulatory Networks ◽

Drug Response ◽

Human Cancer ◽

Regulation Mechanism ◽

Aberrant Expression ◽

Chromatin Remodeling Complexes ◽

And Function

AbstractDisordered chromatin remodeling regulation has emerged as an essential driving factor for cancers. Imitation switch (ISWI) family are evolutionarily conserved ATP-dependent chromatin remodeling complexes, which are essential for cellular survival and function through multiple genetic and epigenetic mechanisms. Omics sequencing and a growing number of basic and clinical studies found that ISWI family members displayed widespread gene expression and genetic status abnormalities in human cancer. Their aberrant expression is closely linked to patient outcome and drug response. Functional or componential alteration in ISWI-containing complexes is critical for tumor initiation and development. Furthermore, ISWI-non-coding RNA regulatory networks and some non-coding RNAs derived from exons of ISWI member genes play important roles in tumor progression. Therefore, unveiling the transcriptional regulation mechanism underlying ISWI family sparked a booming interest in finding ISWI-based therapies in cancer. This review aims at describing the current state-of-the-art in the role of ISWI subunits and complexes in tumorigenesis, tumor progression, immunity and drug response, and presenting deep insight into the physiological and pathological implications of the ISWI transcription machinery in cancers.

Download Full-text

Cardiac enriched BAF chromatin remodeling complex subunit Baf60c regulates gene expression programs essential for heart development and function

10.1101/184143 ◽

2017 ◽

Author(s):

Xin Sun ◽

Swetansu K. Hota ◽

Yu-Qing Zhou ◽

Stefanie Novak ◽

Dario Miguel-Perez ◽

...

Keyword(s):

Gene Expression ◽

Chromatin Remodeling ◽

Heart Development ◽

Gene Networks ◽

Contractile Function ◽

Conditional Deletion ◽

Genes Encoding ◽

Organ Specific ◽

Chromatin Remodeling Complexes ◽

And Function

AbstractHow gene networks controlling organ-specific properties are modulated by chromatin remodeling complexes is not well understood. Baf60c (Smarcd3) encodes a cardiac-enriched subunit of the SWI/SNF-like BAF chromatin complex. Its role throughout heart development is not fully understood. We show that constitutive loss of Baf60c leads to embryonic cardiac hypoplasia and pronounced cardiac dysfunction. Conditional deletion of Baf60c in cardiomyocytes results in postnatal dilated cardiomyopathy with impaired contractile function. Baf60c regulates a gene expression program that includes genes encoding contractile proteins, modulators of sarcomere function, and cardiac metabolic genes. Many of the genes deregulated in Baf60c null embryos are targets of the MEF2/SRF co-factor Myocardin (MYOCD). In a yeast two-hybrid screen we identify MYOCD as a BAF60c interacting factor; we show that BAF60c and MYOCD directly and functionally interact. We conclude that Baf60c is essential for coordinating a program of gene expression that regulates the fundamental functional properties of cardiomyocytes.

Download Full-text

Comparative Analysis of SWIRM Domain-Containing Proteins in Plants

Comparative and Functional Genomics ◽

10.1155/2012/310402 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Yan Gao ◽

Songguang Yang ◽

Lianyu Yuan ◽

Yuhai Cui ◽

Keqiang Wu

Keyword(s):

Chromatin Remodeling ◽

Essential Role ◽

Atp Hydrolysis ◽

Chromatin Modification ◽

Dna Binding Proteins ◽

Plant Responses ◽

Chromosomal Proteins ◽

Genes Encoding ◽

Chromatin Remodeling Complexes ◽

Affect Gene Expression

Chromatin-remodeling complexes affect gene expression by using the energy of ATP hydrolysis to locally disrupt or alter the association of histones with DNA. SWIRM (Swi3p, Rsc8p, and Moira) domain is an alpha-helical domain of about 85 residues in chromosomal proteins. SWIRM domain-containing proteins make up large multisubunit complexes by interacting with other chromatin modification factors and may have an important function in plants. However, little is known about SWIRM domain-containing proteins in plants. In this study, 67 SWIRM domain-containing proteins from 6 plant species were identified and analyzed. Plant SWIRM domain proteins can be divided into three distinct types: Swi-type, LSD1-type, and Ada2-type. Generally, the SWIRM domain forms a helix-turn-helix motif commonly found in DNA-binding proteins. The genes encoding SWIRM domain proteins inOryza sativaare widely expressed, especially in pistils. In addition,OsCHB701andOsHDMA701were downregulated by cold stress, whereasOsHDMA701andOsHDMA702were significantly induced by heat stress. These observations indicate that SWIRM domain proteins may play an essential role in plant development and plant responses to environmental stress.

Download Full-text

Reversing the oncogenic roles of misdirected chromatin remodeling: Mechanistic insights into the SS18-SSX fusion protein in synovial sarcoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.10515 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 10515-10515

Author(s):

Cigall Kadoch ◽

Gerald R. Crabtree

Keyword(s):

Amino Acids ◽

Synovial Sarcoma ◽

Chromatin Remodeling ◽

Affinity Purification ◽

Cell Types ◽

Molecular Feature ◽

C Terminus ◽

Therapeutic Development ◽

Chromatin Remodeling Complexes ◽

Rhabdoid Tumors

10515 Background: Synovial sarcoma (SS) accounts for ~10% of soft-tissue malignancies and is generally resistant to chemotherapy-based approaches, underscoring the need for a mechanistic understanding of its pathogenesis and the development of disease-specific biologic agents. The hallmark molecular feature is a precise and uniform translocation, t(X;18), which results in the fusion of exactly 78 amino acids of SSX to the SS18 C-terminus. Because the SS18-SSX genetic lesion is observed in 100% of cases, it is likely the driving oncogenic event in these tumors; however, the molecular basis for its role in oncogenesis is undefined. Methods: We performed an affinity purification-/mass spectrometry-based analysis of endogenous mSWI/SNF (BAF) chromatin remodeling complexes in several primary cell types. Using these data in combination with protein biochemical methods, we discovered that SS18 is a dedicated, non-exchangeable subunit of these complexes with a binding affinity comparable to that of ribosomal subunits. Subsequent biochemical and functional investigations were performed to assess the oncogenic consequences of addition of 78aa of SSX to the SS18 subunit in SS. Results: We demonstrate that the SS18-SSX fusion incorporates into BAF complexes, evicting both wild-type (WT) SS18 and the tumor suppressor subunit, hSNF5 (BAF47), known to be biallelically inactivated in pediatric malignant rhabdoid tumors (MRTs). The altered complex binds the Sox2 locus, reversing polycomb-mediated repression and activating Sox2. Sox2, a pro-pluripotency transcription factor, is uniformly expressed in SS tumors and is essential for proliferation. Remarkably, increasing the concentration of WT SS18 leads to reassembly of WT complexes, retargeting of BAF complexes, returned polycomb-mediated repression at the Sox2 locus and cessation of SS cell proliferation. This mechanism of transformation depends on a region of only two amino acids of SSX, and hence provides a strong foundation for therapeutic intervention. Conclusions: These studies provide a novel oncogenic mechanism for SS tumors and inform strategies for therapeutic development in this intractable cancer.

Download Full-text

Functional diversity of ISWI complexes

Biochemistry and Cell Biology ◽

10.1139/o04-044 ◽

2004 ◽

Vol 82 (4) ◽

pp. 482-489 ◽

Cited By ~ 59

Author(s):

Sara S Dirscherl ◽

Jocelyn E Krebs

Keyword(s):

Chromatin Remodeling ◽

Catalytic Core ◽

Chromatin Remodelers ◽

Form And Function ◽

Curr Opin Cell Biol ◽

Chromatid Cohesion ◽

Chromatin Remodeling Complexes ◽

And Function ◽

Diverse Groups ◽

Nuclear Processes

The yeast SWI/SNF ATP-dependent chromatin remodeling complex was first identified and characterized over 10 years ago (F. Winston and M. Carlson. 1992. Trends Genet. 8: 387–391.) Since then, the number of distinct ATP-dependent chromatin remodeling complexes and the variety of roles they play in nuclear processes have become dizzying (J.A. Martens and F. Winston. 2003. Curr. Opin. Genet. Dev. 13: 136–142; A. Vacquero et al. 2003. Sci. Aging Knowledge Environ. 2003: RE4) — and that does not even include the companion suite of histone modifying enzymes, which exhibit a comparable diversity in both number of complexes and variety of functions (M.J. Carrozza et al. 2003. Trends Genet. 19: 321–329; W. Fischle et al. 2003. Curr. Opin. Cell Biol. 15: 172–183; M. Iizuka and M.M. Smith. 2003. Curr. Opin. Genet. Dev. 13: 1529–1539). This vast complexity is hardly surprising, given that all nuclear processes that involve DNA — transcription, replication, repair, recombination, sister chromatid cohesion, etc. — must all occur in the context of chromatin. The SWI/SNF-related ATP-dependent remodelers are divided into a number of subfamilies, all related by the SWI2/SNF2 ATPase at their catalytic core. In nearly every species where researchers have looked for them, one or more members of each subfamily have been identified. Even the budding yeast, with its comparatively small genome, contains eight different chromatin remodelers in five different subfamilies. This review will focus on just one subfamily, the Imitation Switch (ISWI) family, which is proving to be one of the most diverse groups of chromatin remodelers in both form and function.

Download Full-text

Connection between histone H2A variants and chromatin remodeling complexesThis paper is one of a selection of papers published in this Special Issue, entitled CSBMCB’s 51st Annual Meeting – Epigenetics and Chromatin Dynamics, and has undergone the Journal’s usual peer review process.

Biochemistry and Cell Biology ◽

10.1139/o08-140 ◽

2009 ◽

Vol 87 (1) ◽

pp. 35-50 ◽

Cited By ~ 47

Author(s):

Mohammed Altaf ◽

Andréanne Auger ◽

Marcela Covic ◽

Jacques Côté

Keyword(s):

Chromatin Remodeling ◽

Chromatin Structure ◽

Cellular Response ◽

Peer Review Process ◽

Histone Variants ◽

Histone H2a ◽

Chromatin Dynamics ◽

Recent Developments ◽

Chromatin Remodeling Complexes ◽

And Function

The organization of the eukaryotic genome into chromatin makes it inaccessible to the factors required for gene transcription and DNA replication, recombination, and repair. In addition to histone-modifying enzymes and ATP-dependent chromatin remodeling complexes, which play key roles in regulating many nuclear processes by altering the chromatin structure, cells have developed a mechanism of modulating chromatin structure by incorporating histone variants. These variants are incorporated into specific regions of the genome throughout the cell cycle. H2A.Z, which is an evolutionarily conserved H2A variant, performs several seemingly unrelated and even contrary functions. Another H2A variant, H2A.X, plays a very important role in the cellular response to DNA damage. This review summarizes the recent developments in our understanding of the role of H2A.Z and H2A.X in the regulation of chromatin structure and function, focusing on their functional links with chromatin modifying and remodeling complexes.

Download Full-text

Chromatin remodeling factor CECR2 forms tissue-specific complexes with CCAR2 and LUZP1

Biochemistry and Cell Biology ◽

10.1139/bcb-2021-0019 ◽

2021 ◽

Author(s):

Farshad Niri ◽

Alaina Terpstra ◽

Kenji Rowel Quintana Lim ◽

Heather McDermid

Keyword(s):

Chromatin Remodeling ◽

Neural Tube ◽

Es Cells ◽

Embryonic Stem ◽

Neural Tube Closure ◽

Loss Of Function ◽

Cellular Processes ◽

Novel Proteins ◽

Chromatin Remodeling Complexes ◽

And Function

Chromatin remodeling complexes alter chromatin structure to control access to DNA and therefore control cellular processes such as transcription, DNA replication, and DNA repair. CECR2 is a chromatin remodeling factor that plays an important role in neural tube closure and reproduction. Loss-of-function mutations in Cecr2 result primarily in the perinatal lethal neural tube defect exencephaly, with non-penetrant mice that survive to adulthood exhibiting subfertility. CECR2 forms a complex with ISWI proteins SMARCA5 and/or SMARCA1, but further information on the structure and function of the complex is not known. We therefore have identified candidate components of the CECR2-containing remodeling factor (CERF) complex in embryonic stem (ES) cells through mass spectroscopy. Both SMARCA5 and SMARCA1 were confirmed to be present in CERF complexes in ES cells and testis. However, novel proteins CCAR2 and LUZP1 are CERF components in ES cells but not testis. This tissue specificity in mice suggests these complexes may also have functional differences. Furthermore, LUZP1, loss of which is also associated with exencephaly, appears to play a role in stabilizing the CERF complex in ES cells. Keywords: CECR2, LUZP1, CCAR2, Chromatin remodeling factor, Neural tube defects

Download Full-text