Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for activation and repression of transcription

TY - JOUR

T1 - Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for activation and repression of transcription

AU - Blümli, Seraina

AU - Wiechens, Nicola

AU - Wu, Meng-Ying

AU - Singh, Vijender

AU - Gierlinski, Marek

AU - Schweikert, Gabriele

AU - Gilbert, Nick

AU - Naughton, Catherine

AU - Sundaramoorthy, Ramasubramanian

AU - Varghese, Joby

AU - Gourlay, Robert

AU - Soares, Renata

AU - Clark, David

AU - Owen-Hughes, Tom

N1 - This work was funded by MRC grant MR/SO21647/1 and CRUK studentship C1195/A17994.

PY - 2021/11/2

Y1 - 2021/11/2

N2 - The 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.

AB - The 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.

KW - ARID1A

KW - SWI/SNF

KW - EP300

KW - BAF

KW - chromatin remodeling

KW - nucleosomes

KW - enhancer transcription

KW - cancer

UR - https://www.scopus.com/pages/publications/85118511462

U2 - 10.1016/j.celrep.2021.109943

DO - 10.1016/j.celrep.2021.109943

M3 - Article

C2 - 34731603

SN - 2211-1247

VL - 37

JO - Cell Reports

JF - Cell Reports

IS - 5

M1 - 109943

ER -