Abstract
SummaryThe ARID1A subunit of SWI/SNF chromatin remodeling complexes is a potent tumor suppressor. Here, a degron is applied to detect rapid loss of chromatin accessibility at thousands of loci where ARID1A acts to generate accessible minidomains of nucleosomes. Loss of ARID1A also results in the redistribution of the coactivator EP300. Co-incident EP300 dissociation and lost chromatin accessibility at enhancer elements are highly enriched adjacent to rapidly downregulated genes. In contrast, sites of gained EP300 occupancy are linked to genes that are transcriptionally upregulated. These chromatin changes are associated with a small number of genes that are differentially expressed in the first hours following loss of ARID1A. Indirect or adaptive changes dominate the transcriptome following growth for days after loss of ARID1A and result in strong engagement with cancer pathways. The identification of this hierarchy suggests sites for intervention in ARID1A-driven diseases.
Highlights
One of the ways by which eukaryotes regulate chromatin structure is through the action of ATP-dependent chromatin remodeling activities (Narlikar et al, 2013)
Engineering mouse embryonic stem cell (ESC) for rapid depletion of ARID1A from SWI/SNF complexes In order to define direct targets affected by loss of function of mammalian SWI/SNF complexes, a degron strategy was adopted
The endogenous ARID1A gene was homozygously tagged with the mini-auxin-induced degron targeting peptide and GFP (Natsume et al, 2016) in a mouse embryonic stem cell (ESC)
Summary
One of the ways by which eukaryotes regulate chromatin structure is through the action of ATP-dependent chromatin remodeling activities (Narlikar et al, 2013). In mammals there are three main forms of the complex with distinct subunit compositions (Mashtalir et al, 2018) Mutations to these complexes have long been recognized as causing alterations to the transcription of a subset of genes. Depletion of the Snf paralog Sth results in rapid organization of chromatin at nucleosome-free promoter regions (Ganguli et al, 2014; Klein-Brill et al, 2019) This is associated with a shift in the position of the +1 nucleosome toward promoters affecting adjacent coding region nucleosomes but relatively minor primary defects to transcription (Klein-Brill et al, 2019)
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