NSD1 mediates antagonism between SWI/SNF and polycomb complexes and is required for transcriptional activation upon EZH2 inhibition

Drosos, Yiannis; Myers, Jason; Xu, Beisi; Mathias, Kaeli M.; Beane, Emma C.; Radko-Juettner, Sandi; Mobley, Robert J.; Larsen, Margaret E.; Piccioni, Federica; Ma, Xiaotu; Low, Jonathan; Hansen, Baranda S.; Peters, Samuel; Bhanu, Natarajan V.; Dhanda, Sandeep Kumar; Chen, Taosheng; Upadhyaya, Santhosh A.; Pruett-Miller, Shondra M.; Root, David E.; García, Benjamin A.; Partridge, Janet F.; Roberts, Charles W.M.

doi:10.1016/j.molcel.2022.04.015

Cited by 30 publications

(16 citation statements)

References 76 publications

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“…CUT & RUN was performed using the Epicypher (Durham, NC) Cutana Cut&Run Kit v2.0 according to the manufacturer’s protocol as reported (Drosos et al 2022). Briefly, permeabilization was achieved using 0.08% digitonin (Cell Signaling Technology #16359).…”

Section: Methodsmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted August 7, 2022. ; https://doi.org/10.1101/2022.08.07.503080 doi: bioRxiv preprint CUT & RUN was performed using the Epicypher (Durham, NC) Cutana Cut&Run Kit v2.0 according to the manufacturer's protocol as reported (Drosos et al 2022). Briefly, permeabilization was achieved using 0.08% digitonin (Cell Signaling Technology #16359).…”

Section: Cut and Runmentioning

confidence: 99%

“…Generation of SMARCB1-inducible G401 cells G401 cells expressing TET3G regulatory protein with doxycycline-inducible SMARCB1 or GFP were generated as described in (Drosos et al, 2022).…”

Section: Lentivirusmentioning

confidence: 99%

“…Libraries were prepared by using the KAPA HyperPrep kit (Roche, Basel, Switzerland, # 7962363001) according to the manufacturer's specifications, and library quality was determined by using the TapeStation (Agilent) with D1000 screentape. Then, >100k 50-bp paired-end reads per sample were generated on the NovaSeq 6000.CUT & RUNCUT & RUN was performed using the Epicypher (Durham, NC) Cutana Cut&Run Kit v2.0 according to the manufacturer's protocol as reported(Drosos et al 2022). Briefly, permeabilization was achieved using 0.08% digitonin (Cell Signaling Technology #16359).…”

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confidence: 99%

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Functional interplay between SWI/SNF complexes underlies BRD9 dependency in SMARCB1-mutant cancers

Mobley

Myers

Wills

et al. 2022

Preprint

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Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in >20% of cancers. SWI/SNF complexes exist in three distinct families that each contribute to regulation of transcription, although the functional interactions between the families are not well understood. Rhabdoid tumors constitute an informative model system as these highly aggressive cancers are driven by inactivation of a single SWI/SNF subunit, SMARCB1, which is present in two SWI/SNF families (cBAF and PBAF) but not in the third (GBAF/ncBAF). We and others have shown that BRD9, a therapeutically targetable member of ncBAF, is essential specifically in SMARCB1-deficient cancers, suggesting key functional relationships between SMARCB1-containing complexes and BRD9/ncBAF. However, the mechanistic underpinnings of these relationships are poorly understood. Here, we demonstrate that genomic binding of BRD9 is largely dependent upon SMARCB1 such that the absence of SMARCB1 results in significantly reduced BRD9 binding. At select sites, however, we show that SMARCB1-loss results in gain of BRD9 binding and BRD9-dependent accessibility. We find that this gain is associated with expression of genes promoting cell migration. Our results define relationships between SWI/SNF complex families, elucidate mechanisms by which SMARCB1 loss drives oncogenesis, and provide mechanistic insight into the synthetic-lethal relationship between SMARCB1 and BRD9.

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Section: Methodsmentioning

confidence: 99%

Section: Cut and Runmentioning

confidence: 99%

“…Generation of SMARCB1-inducible G401 cells G401 cells expressing TET3G regulatory protein with doxycycline-inducible SMARCB1 or GFP were generated as described in (Drosos et al, 2022).…”

Section: Lentivirusmentioning

confidence: 99%

mentioning

confidence: 99%

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Functional interplay between SWI/SNF complexes underlies BRD9 dependency in SMARCB1-mutant cancers

Mobley

Myers

Wills

et al. 2022

Preprint

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“…This is best highlighted by the fact that PRC2 and PR-DUB have both gain-and loss-of-function mutations in different cancer contexts (Morin et al, 2010;Ntziachristos et al, 2012;Balasubramani et al, 2015;Conway et al, 2021). Indeed, efficacy of EZH2 inhibitors in malignant rhabdoid tumours is dependent on the activity of NSD1, reinforcing the importance of this balance of Polycomb and H3K36me2 domains across different cancers (Drosos et al, 2022). The precise contribution of broad histone modification domains, largely devoid of epigenetic complex binding, remain unknown.…”

Section: Polycomb Domain Erosionmentioning

confidence: 99%

Know when to fold ‘em: Polycomb complexes in oncogenic 3D genome regulation

Doyle

Morey

Conway

2022

Front. Cell Dev. Biol.

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Chromatin is spatially and temporally regulated through a series of orchestrated processes resulting in the formation of 3D chromatin structures such as topologically associating domains (TADs), loops and Polycomb Bodies. These structures are closely linked to transcriptional regulation, with loss of control of these processes a frequent feature of cancer and developmental syndromes. One such oncogenic disruption of the 3D genome is through recurrent dysregulation of Polycomb Group Complex (PcG) functions either through genetic mutations, amplification or deletion of genes that encode for PcG proteins. PcG complexes are evolutionarily conserved epigenetic complexes. They are key for early development and are essential transcriptional repressors. PcG complexes include PRC1, PRC2 and PR-DUB which are responsible for the control of the histone modifications H2AK119ub1 and H3K27me3. The spatial distribution of the complexes within the nuclear environment, and their associated modifications have profound effects on the regulation of gene transcription and the 3D genome. Nevertheless, how PcG complexes regulate 3D chromatin organization is still poorly understood. Here we glean insights into the role of PcG complexes in 3D genome regulation and compaction, how these processes go awry during tumorigenesis and the therapeutic implications that result from our insights into these mechanisms.

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(mis)-Targeting of SWI/SNF complex(es) in cancer

Reddy

Bhattacharya

Workman

2023

Cancer Metastasis Rev

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The ATP-dependent chromatin remodeling complex SWI/SNF (also called BAF) is critical for the regulation of gene expression. During the evolution from yeast to mammals, the BAF complex has evolved an enormous complexity that contains a high number of subunits encoded by various genes. Emerging studies highlight the frequent involvement of altered mammalian SWI/SNF chromatin-remodeling complexes in human cancers. Here, we discuss the recent advances in determining the structure of SWI/SNF complexes, highlight the mechanisms by which mutations affecting these complexes promote cancer, and describe the promising emerging opportunities for targeted therapies.

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NSD1 mediates antagonism between SWI/SNF and polycomb complexes and is required for transcriptional activation upon EZH2 inhibition

Cited by 30 publications

References 76 publications

Functional interplay between SWI/SNF complexes underlies BRD9 dependency in SMARCB1-mutant cancers

Functional interplay between SWI/SNF complexes underlies BRD9 dependency in SMARCB1-mutant cancers

Know when to fold ‘em: Polycomb complexes in oncogenic 3D genome regulation

(mis)-Targeting of SWI/SNF complex(es) in cancer

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