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

2015 ◽  
Vol 1 (5) ◽  
pp. e1500447 ◽  
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.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-48-SCI-48
Author(s):  
Cigall Kadoch
Keyword(s):  
Chromatin Remodeling ◽  
Developmental Disorders ◽  
Human Cancer ◽  
Malignant Rhabdoid Tumor ◽  
Advisory Committees ◽  
Sequencing Studies ◽  
Genes Encoding ◽  
Therapeutic Development ◽  
Chromatin Remodeling Complexes ◽  
And Function

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.

scholarly journals GBAF, a small BAF sub-complex with big implications: a systematic review

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Sarah M. Innis ◽  
Birgit Cabot
Keyword(s):  
Chromatin Remodeling ◽  
Cellular Differentiation ◽  
Complex Function ◽  
Therapeutic Interventions ◽  
Mammalian Development ◽  
Aberrant Expression ◽  
Chromatin Remodelers ◽  
Baf Complex ◽  
Chromatin Remodeling Complexes ◽  
Histone Modifying Enzymes

Abstract ATP-dependent chromatin remodeling by histone-modifying enzymes and chromatin remodeling complexes is crucial for maintaining chromatin organization and facilitating gene transcription. In the SWI/SNF family of ATP-dependent chromatin remodelers, distinct complexes such as BAF, PBAF, GBAF, esBAF and npBAF/nBAF are of particular interest regarding their implications in cellular differentiation and development, as well as in various diseases. The recently identified BAF subcomplex GBAF is no exception to this, and information is emerging linking this complex and its components to crucial events in mammalian development. Furthermore, given the essential nature of many of its subunits in maintaining effective chromatin remodeling function, it comes as no surprise that aberrant expression of GBAF complex components is associated with disease development, including neurodevelopmental disorders and numerous malignancies. It becomes clear that building upon our knowledge of GBAF and BAF complex function will be essential for advancements in both mammalian reproductive applications and the development of more effective therapeutic interventions and strategies. Here, we review the roles of the SWI/SNF chromatin remodeling subcomplex GBAF and its subunits in mammalian development and disease.

scholarly journals Comparative Analysis of SWIRM Domain-Containing Proteins in Plants

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
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.

scholarly journals Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Young Seok Ju ◽  
Ludmil B Alexandrov ◽  
Moritz Gerstung ◽  
Inigo Martincorena ◽  
Serena Nik-Zainal ◽  
...  
Keyword(s):  
Human Cancer ◽  
Missense Mutations ◽  
Mtdna Mutations ◽  
Dna Mutations ◽  
Mtdna Sequence ◽  
Sequencing Studies ◽  
Functional Consequences ◽  
Somatic Alterations ◽  
Mtdna Replication ◽  
Tumor Types

Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.

Functional diversity of ISWI complexes

2004 ◽  
Vol 82 (4) ◽  
pp. 482-489 ◽  
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.

scholarly journals The emerging role of ISWI chromatin remodeling complexes in cancer

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.

scholarly journals Diverse compositions and functions of chromatin remodeling machines in cancer

2019 ◽  
Vol 11 (501) ◽  
pp. eaay1018 ◽  
Author(s):  
Cigall Kadoch
Keyword(s):  
Chromatin Remodeling ◽  
Cancer Genetics ◽  
Human Cancer ◽  
Chromatin Remodeling Complexes

Human cancer genetics power biochemical and functional interrogation of chromatin remodeling complexes, informing therapeutic opportunities.

How many remodelers does it take to make a brain? Diverse and cooperative roles of ATP-dependent chromatin-remodeling complexes in developmentThis paper is one of a selection of papers published in this Special Issue, entitled 28th International West Coast Chromatin and Chromosome Conference, and has undergone the Journal's usual peer review process.

2007 ◽  
Vol 85 (4) ◽  
pp. 444-462 ◽  
Author(s):  
Elvin Brown ◽  
Sreepurna Malakar ◽  
Jocelyn E. Krebs
Keyword(s):  
Chromatin Remodeling ◽  
Dna Sequences ◽  
Protein Complexes ◽  
Peer Review Process ◽  
Chromatin Remodelers ◽  
Dna Accessibility ◽  
Stage Of Development ◽  
Chromatin Remodeling Complexes ◽  
Cellular Machinery ◽  
Selection Of

The development of a metazoan from a single-celled zygote to a complex multicellular organism requires elaborate and carefully regulated programs of gene expression. However, the tight packaging of genomic DNA into chromatin makes genes inaccessible to the cellular machinery and must be overcome by the processes of chromatin remodeling; in addition, chromatin remodeling can preferentially silence genes when their expression is not required. One class of chromatin remodelers, ATP-dependent chromatin-remodeling enzymes, can slide nucleosomes along the DNA to make specific DNA sequences accessible or inaccessible to regulators at a particular stage of development. While all ATPases in the SWI2/SNF2 superfamily share the fundamental ability to alter DNA accessibility in chromatin, they do not act alone, but rather, are subunits of a large assortment of protein complexes. Recent studies illuminate common themes by which the subunit compositions of chromatin-remodeling complexes specify the developmental roles that chromatin remodelers play in specific tissues and at specific stages of development, in response to specific signaling pathways and transcription factors. In this review, we will discuss the known roles in metazoan development of 3 major subfamilies of chromatin-remodeling complexes: the SNF2, ISWI, and CHD subfamilies.

scholarly journals The INO80 Chromatin Remodeler Sustains Metabolic Stability by Promoting TOR Signaling and Regulating Histone Acetylation

2017 ◽  
Author(s):  
Sean L. Beckwith ◽  
Erin K. Schwartz ◽  
Pablo E. Garcia-Nieto ◽  
Devin A. King ◽  
Graeme J. Gowans ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Chromatin Remodeling ◽  
Cell Function ◽  
Metabolic Stability ◽  
Central Component ◽  
Metabolic Homeostasis ◽  
Tor Signaling ◽  
Chromatin Remodelers ◽  
Chromatin Remodeling Complexes ◽  
Metabolic Regulators

ABSTRACTChromatin remodeling complexes are essential for gene expression programs that coordinate cell function with metabolic status. However, how these remodelers are integrated in metabolic stability pathways is not well known. Here, we report an expansive genetic screen with chromatin remodelers and metabolic regulators in Saccharomyces cerevisiae. We found that, unlike the SWR1 remodeler, the INO80 chromatin remodeling complex is composed of multiple distinct functional subunit modules. We identified a strikingly divergent genetic signature for the Ies6 subunit module that links the INO80 complex to metabolic homeostasis, including mitochondrial maintenance. INO80 is also needed to communicate TORC1-mediated signaling to chromatin and maintains histone acetylation at TORC1-responsive genes. Furthermore, computational analysis reveals subunits of INO80 and mTORC1 have high co-occurrence of alterations in human cancers. Collectively, these results demonstrate that the INO80 complex is a central component of metabolic homeostasis that influences histone acetylation and may contribute to disease when disrupted.

scholarly journals ARID1A loss in neuroblastoma promotes the adrenergic-to-mesenchymal transition by regulating enhancer-mediated gene expression

2020 ◽  
Vol 6 (29) ◽  
pp. eaaz3440 ◽  
Author(s):  
Hui Shi ◽  
Ting Tao ◽  
Brian J. Abraham ◽  
Adam D. Durbin ◽  
Mark W. Zimmerman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromatin Remodeling ◽  
Neuroblastoma Cells ◽  
Tumor Development ◽  
Mesenchymal Cell ◽  
Drug Resistant ◽  
Zebrafish Model ◽  
Mesenchymal Transition ◽  
Genes Encoding ◽  
Chromatin Remodeling Complexes

Mutations in genes encoding SWI/SNF chromatin remodeling complexes are found in approximately 20% of all human cancers, with ARID1A being the most frequently mutated subunit. Here, we show that disruption of ARID1A homologs in a zebrafish model accelerates the onset and increases the penetrance of MYCN-driven neuroblastoma by increasing cell proliferation in the sympathoadrenal lineage. Depletion of ARID1A in human NGP neuroblastoma cells promoted the adrenergic-to-mesenchymal transition with changes in enhancer-mediated gene expression due to alterations in the genomic occupancies of distinct SWI/SNF assemblies, BAF and PBAF. Our findings indicate that ARID1A is a haploinsufficient tumor suppressor in MYCN-driven neuroblastoma, whose depletion enhances tumor development and promotes the emergence of the more drug-resistant mesenchymal cell state.

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