Author response: Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers

Kelso, Timothy W. R.; Porter, Devin K.; Amaral, Maria Luisa; Shokhirev, Maxim N.; Benner, Christopher; Hargreaves, Diana C.

doi:10.7554/elife.30506.054

Cited by 6 publications

(2 citation statements)

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“…Loss-of-function mutations in ARID1A are frequently found in human cancers and the molecular functions of ARID1A in cancer cells are being unraveled (Kadoch and Crabtree, 2015). ARID1A has been proposed to maintain transcriptional activity by recruiting EP300 acetyltransferase to enhancers (Alver et al, 2017;Mathur et al, 2017) or by controlling chromatin accessibility at enhancers (Kelso et al, 2017). A recent study, however, found that ARID1A depletion only modestly altered accessibility and proposed that ARID1A maintains RNA polymerase pausing near transcriptional start sites to enable robust transcription during homeostasis (Trizzino et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…To gain mechanistic insights into the axon guidance role of Arid1a, we sought to explore its molecular functions. As a chromatin remodeler, ARID1A mediates transcriptional regulation (Alver et al, 2017;Kelso et al, 2017;Mathur et al, 2017;Trizzino et al, 2018). To determine the potential influence of Arid1a deletion on gene expression, we analyzed the transcriptomes of cKO-E and littermate control cortices at E15.5, a developmental stage when intracortical and thalamocortical axons undergo extension and pathfinding to reach their targets (Anton-Bolanos et al, 2018;Auladell et al, 2000;Ozaki and Wahlsten, 1992).…”

Section: Selective Disruption Of Subplate Neuron Gene Expression Follmentioning

confidence: 99%

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Chromatin remodelerArid1aregulates subplate neuron identity and wiring of cortical connectivity

Doyle

Lam

Qalieh

et al. 2020

Preprint

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Subplate neurons indispensably orchestrate the developmental assembly of cortical neural circuits. Here, by cell type-specific dissection of Arid1a function, we uncover an unexpectedly selective role for this ubiquitous chromatin remodeler in subplate neuron molecular identity and circuit wiring function. We find that pan-cortical deletion of Arid1a, but not sparse deletion, leads to mistargeting of callosal and thalamocortical connectivities reminiscent of subplate ablation. These miswiring phenotypes are concomitant with disrupted subplate neuron organization, morphogenesis, axons, and extracellular matrix. Mechanistically, Arid1a is required to establish the transcriptional identity of subplate neurons. Remarkably, cortical plate deletion of Arid1a, which spares subplate neurons, restores subplate axons and extracellular matrix, and is sufficient to extensively correct callosal and thalamocortical axon misrouting, revealing an axon guidance function of Arid1a centered on the subplate. Thus, Arid1a regulates the molecular identity and function of subplate neurons, and thereby non-cell autonomously mediates the formation of cortical connectivity during development.

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Section: Discussionmentioning

confidence: 99%

Section: Selective Disruption Of Subplate Neuron Gene Expression Follmentioning

confidence: 99%

Chromatin remodelerArid1aregulates subplate neuron identity and wiring of cortical connectivity

Doyle

Lam

Qalieh

et al. 2020

Preprint

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Arid1aloss potentiates pancreatic β-cell regeneration through activation of EGF signaling

Celen

Chuang

Shen

et al. 2020

Preprint

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The dynamic regulation of β-cell abundance is poorly understood. Since chromatin remodeling plays critical roles in liver regeneration, these mechanisms could be generally important for regeneration in other tissues. Here we show that the ARID1A mammalian SWI/SNF complex subunit is a critical regulator of β-cell regeneration. Arid1a is highly expressed in quiescent β-cells but is physiologically suppressed when β-cells proliferate during pregnancy or after pancreas resection. Whole-body Arid1a knockout mice were protected against streptozotocin induced diabetes. Cell-type and temporally specific genetic dissection showed that β-cell specific Arid1a deletion could potentiate β-cell regeneration in multiple contexts. Transcriptomic and epigenomic profiling of mutant islets revealed increased Neuregulin-ERBB-NR4A signaling.Functionally, ERBB3 overexpression in β-cells was sufficient to protect against diabetes, and chemical inhibition of ERBB or NR4A was able to block increased regeneration associated with Arid1a loss. mSWI/SNF complex activity is a barrier to β-cell regeneration in physiologic and disease states.

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Chromatin accessibility changes induced by the microbial metabolite butyrate reveal possible mechanisms of anti-cancer effects

et al. 2021

Preprint

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Butyrate is a four-carbon fatty acid produced in large quantities by bacteria found in the human gut. It is the major source of colonic epithelial cell energy, can bind to and agonize short-chain fatty acid G-protein coupled receptors and functions as a histone deacetylase (HDAC) inhibitor. Anti-cancer effects of butyrate are attributed to a global increase in histone acetylation in colon cancer cells; however, the role that corresponding chromatin remodeling plays in this effect is not fully understood. We used longitudinal paired ATAC-seq and RNA-seq on HCT-116 colon cancer cells to determine how butyrate-related chromatin changes functionally associate with cancer. We detected distinct temporal changes in chromatin accessibility in response to butyrate with less accessible regions enriched in transcription factor binding motifs and distal enhancers. These regions significantly overlapped with regions maintained by the SWI/SNF chromatin remodeler, and were further enriched amongst chromatin regions that are associated with ARID1A/B synthetic lethality. Finally, we found that butyrate-induced chromatin regions were enriched for both colorectal cancer GWAS loci and somatic mutations in cancer. These results demonstrate the convergence of both somatic mutations and GWAS risk variants for colon cancer within butyrate-responsive chromatin regions, providing a molecular map of the mechanisms by which this microbial metabolite might confer anti-cancer properties.

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Author response: Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers

Cited by 6 publications

References 0 publications

Chromatin remodelerArid1aregulates subplate neuron identity and wiring of cortical connectivity

Chromatin remodelerArid1aregulates subplate neuron identity and wiring of cortical connectivity

Arid1aloss potentiates pancreatic β-cell regeneration through activation of EGF signaling

Chromatin accessibility changes induced by the microbial metabolite butyrate reveal possible mechanisms of anti-cancer effects

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