Vulnerabilities of Mutant SWI/SNF Complexes in Cancer

Helming, Katherine; Wang, Xiaofeng; Roberts, Charles W.M.

doi:10.1016/j.ccr.2014.07.018

Cited by 239 publications

(239 citation statements)

References 104 publications

(144 reference statements)

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“…In addition, inactivating mutations in Brg1 and other subunits of SWI/SNF complexes have been identified in various human cancers, including the pancreas and intestine (Helming et al, 2014;Wilson and Roberts, 2011). Furthermore, Brg1 is involved in cell proliferation during embryonic development (Hang et al, 2010;Seo et al, 2005;Li et al, 2013), a period in which Brg1 depletion increases the number of proliferative cells in neural plate (Seo et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…SWI/SNF (Switch/sucrose non-fermentable) complexes are evolutionarily conserved ATP-dependent chromatin remodeling complexes consisting of multiple protein subunits. Mammalian SWI/SNF complexes contain either of two mutually exclusive catalytic ATPase components: Brg1 (also known as Smarca4) or Brm (Smarca2) (Hargreaves and Crabtree, 2011;Helming et al, 2014;Martens and Winston, 2003;Wilson and Roberts, 2011). Brg1 is indispensable for embryonic development.…”

Section: Introductionmentioning

confidence: 99%

“…ATP-dependent chromatin remodeling complexes alter local chromatin structure using energy from ATP hydrolysis. These structural alterations increase or decrease the accessibility of transcriptional factors and thereby activate or repress the expression of specific genes (Hargreaves and Crabtree, 2011;Helming et al, 2014;Martens and Winston, 2003;Wilson and Roberts, 2011). SWI/SNF (Switch/sucrose non-fermentable) complexes are evolutionarily conserved ATP-dependent chromatin remodeling complexes consisting of multiple protein subunits.…”

Section: Introductionmentioning

confidence: 99%

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Brg1 plays an essential role in development and homeostasis of the duodenum through regulation of Notch signaling

et al. 2016

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Brg1, a core subunit of the SWI/SNF chromatin remodeling complex, is essential for development and homeostasis of various organs. However, the functional role of Brg1 in intestinal development and homeostasis, and the underlying molecular mechanism, remain unknown. We found that deletion of Brg1 in the mouse intestine resulted in growth impairment and early death associated with abnormal crypt-villous formation, skewed differentiation into secretory lineage cells, markedly increased apoptosis, and stem cell loss in the duodenum. Furthermore, we found that the Notch signaling pathway was dramatically downregulated in Brg1-deficient duodenum. Remarkably, overexpression of the Notch1 intercellular domain (ICD) partially reversed the prognosis of intestinal Brg1 mutant mice. Notch1 ICD overexpression rescued morphogenesis, prevented over-differentiation into secretory lineage cells, and restored apoptosis to normal levels in Brg1-deficient duodenum, although stem cell loss was not rescued. Our data demonstrate that Brg1 plays an essential role in development and homeostasis, including morphogenesis, stem cell differentiation and cell survival in the duodenum. Mechanistically, the rescue of the intestinal Brg1 mutant phenotype by overexpression of the Notch1 ICD indicates that Notch signaling is a key downstream target that mediates the effects of Brg1.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Brg1 plays an essential role in development and homeostasis of the duodenum through regulation of Notch signaling

et al. 2016

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“…43 The BAF complexes, which we identified as important cofactors of the H3K27 demethylases, are known to be key players in development 2,[19][20][21] and tumor suppression. 19,[44][45][46] Thus, any alteration in the balance among the BAF complexes, H3K27 demethylases, and methyltransferase will result in severe developmental defects and/or diseases such as cancer (Fig. 4C).…”

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confidence: 99%

Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development

et al. 2016

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The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm-associated factor) complexes play essential roles in development. Studies have shown that the loss of individual BAF subunits often affects local chromatin structure and specific transcriptional programs. However, we do not fully understand how BAF complexes function in development because no animal mutant had been engineered to lack entire multi-subunit BAF complexes. Importantly, we recently reported that double conditional knock-out (dcKO) of the BAF155 and BAF170 core subunits in mice abolished the presence of the other BAF subunits in the developing cortex. The generated dcKO mutant provides a novel and powerful tool for investigating how entire BAF complexes affect cortical development. Using this model, we found that BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3. Here, we present further insights into how the scaffolding ability of the BAF155 and BAF170 core subunits maintains the stability of BAF complexes in the forebrain and throughout the embryo during development. Furthermore, we show that the loss of BAF complexes in the above-described model up-regulates H3K27me3 and impairs forebrain development and embryogenesis. These findings improve our understanding of epigenetic mechanisms and their modulation by the chromatin-remodeling SWI/SNF complexes that control embryonic development.

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“…Thus, only by RNAi was it possible to identify a functional redundancy between ham-3 and swsn-2.2 in fertility, vulval induction, and embryonic development. The synthetic phenotypes between SWI/SNF subunits help to understand the function of these chromatin remodelers in different processes, but also present an opportunity for therapies (Helming et al 2014). Today, the emerging CRISPR/ Cas9 approaches to editing the genome might fuel the investigation of functional interactions between specific loss-of-function mutations of SWI/SNF genes (Frøkjaer-Jensen 2013).…”

Section: Discussionmentioning

confidence: 99%

Functional Interplay of Two Paralogs Encoding SWI/SNF Chromatin-Remodeling Accessory Subunits DuringCaenorhabditis elegansDevelopment

et al. 2016

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SWI/SNF ATP-dependent chromatin-remodeling complexes have been related to several cellular processes such as transcription, regulation of chromosomal stability, and DNA repair. The Caenorhabditis elegans gene ham-3 (also known as swsn-2.1) and its paralog swsn-2.2 encode accessory subunits of SWI/SNF complexes. Using RNA interference (RNAi) assays and diverse alleles we investigated whether ham-3 and swsn-2.2 have different functions during C. elegans development since they encode proteins that are probably mutually exclusive in a given SWI/SNF complex. We found that ham-3 and swsn-2.2 display similar functions in vulva specification, germline development, and intestinal cell proliferation, but have distinct roles in embryonic development. Accordingly, we detected functional redundancy in some developmental processes and demonstrated by RNA sequencing of RNAi-treated L4 animals that ham-3 and swsn-2.2 regulate the expression of a common subset of genes but also have specific targets. Cell lineage analyses in the embryo revealed hyper-proliferation of intestinal cells in ham-3 null mutants whereas swsn-2.2 is required for proper cell divisions. Using a proteomic approach, we identified SWSN-2.2-interacting proteins needed for early cell divisions, such as SAO-1 and ATX-2, and also nuclear envelope proteins such as MEL-28. swsn-2.2 mutants phenocopy mel-28 loss-of-function, and we observed that SWSN-2.2 and MEL-28 colocalize in mitotic and meiotic chromosomes. Moreover, we demonstrated that SWSN-2.2 is required for correct chromosome segregation and nuclear reassembly after mitosis including recruitment of MEL-28 to the nuclear periphery.KEYWORDS SWI/SNF; Caenorhabditis elegans; chromatin; development; nuclear envelope C HROMATIN is a dynamic structure required not only for the packaging of large amounts of DNA in the limited space of eukaryotic nuclei, but also for the regulation of gene expression (Ho and Crabtree 2010;Narlikar et al. 2013). SWI/SNF complexes, which are conserved from yeast to mammals, modify the state of the chromatin in an ATPdependent manner and, therefore, the accessibility of distinct proteins to a given DNA region (Hargreaves and Crabtree 2011;Euskirchen et al. 2012). Such activity in the DNA regulates various cellular aspects like proliferation, differentiation, chromosomal stability, and DNA repair (Reisman et al. 2009;Lans et al. 2010;Euskirchen et al. 2011). SWI/SNF complexes are involved in gene-specific regulation since only a low percentage of gene expression (6% in budding yeast, 7.5% in Caenorhabditis elegans) is regulated by these complexes (Holstege et al. 1998;Riedel et al. 2013).A canonical SWI/SNF complex consists of a central ATPase subunit, two or three core components, and several (five to eight) accessory subunits (Hargreaves and Crabtree 2011). While all SWI/SNF complexes include core subunits that are in charge of remodeling nucleosomes (Phelan et al. 1999), the accessory proteins confer specificity to a given complex and their presence varies depending on the ...

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Vulnerabilities of Mutant SWI/SNF Complexes in Cancer

Cited by 239 publications

References 104 publications

Brg1 plays an essential role in development and homeostasis of the duodenum through regulation of Notch signaling

Brg1 plays an essential role in development and homeostasis of the duodenum through regulation of Notch signaling

Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development

Functional Interplay of Two Paralogs Encoding SWI/SNF Chromatin-Remodeling Accessory Subunits DuringCaenorhabditis elegansDevelopment

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