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

Seraina Blümli; Nicola Wiechens; Meng-Ying Wu; Vijender Singh; Marek Gierlinski; Gabriele Schweikert; Nick Gilbert; Catherine Naughton; Ramasubramanian Sundaramoorthy; Joby Varghese; Robert Gourlay; Renata Soares; David Clark; Tom Owen-Hughes

doi:10.1016/j.celrep.2021.109943

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

Seraina Blümli, Nicola Wiechens, Meng-Ying Wu, Vijender Singh, Marek Gierlinski, Gabriele Schweikert, Nick Gilbert, Catherine Naughton, Ramasubramanian Sundaramoorthy, Joby Varghese, Robert Gourlay, Renata Soares, David Clark, Tom Owen-Hughes (Lead / Corresponding author)

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Abstract

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.

Original language	English
Article number	109943
Number of pages	17
Journal	Cell Reports
Volume	37
Issue number	5
Early online date	2 Nov 2021
DOIs	https://doi.org/10.1016/j.celrep.2021.109943
Publication status	Published - 2 Nov 2021

Keywords

ARID1A
SWI/SNF
EP300
BAF
chromatin remodeling
nucleosomes
enhancer transcription
cancer

ASJC Scopus subject areas

General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2021.109943Licence: CC BY

Final published versionFinal published version, 4.69 MBLicence: CC BY

Cite this

Blümli, S., Wiechens, N., Wu, M.-Y., Singh, V., Gierlinski, M., Schweikert, G., Gilbert, N., Naughton, C., Sundaramoorthy, R., Varghese, J., Gourlay, R., Soares, R., Clark, D., & Owen-Hughes, T. (2021). Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for activation and repression of transcription. Cell Reports, 37(5), Article 109943. https://doi.org/10.1016/j.celrep.2021.109943

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

abstract = "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.",

keywords = "ARID1A, SWI/SNF, EP300, BAF, chromatin remodeling, nucleosomes, enhancer transcription, cancer",

author = "Seraina Bl{\"u}mli and Nicola Wiechens and Meng-Ying Wu and Vijender Singh and Marek Gierlinski and Gabriele Schweikert and Nick Gilbert and Catherine Naughton and Ramasubramanian Sundaramoorthy and Joby Varghese and Robert Gourlay and Renata Soares and David Clark and Tom Owen-Hughes",

note = "This work was funded by MRC grant MR/SO21647/1 and CRUK studentship C1195/A17994.",

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Blümli, S , Wiechens, N, Wu, M-Y, Singh, V, Gierlinski, M , Schweikert, G, Gilbert, N, Naughton, C, Sundaramoorthy, R, Varghese, J, Gourlay, R, Soares, R, Clark, D & Owen-Hughes, T 2021, 'Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for activation and repression of transcription', Cell Reports, vol. 37, no. 5, 109943. https://doi.org/10.1016/j.celrep.2021.109943

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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.

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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Structure and Function of Chromatin Remodelling ATPases and their Dysfunction in Human Disease

Dundee Cancer Research UK Centre (Clinical Training Account)

Data Analysis Group

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MRC PPU Reagents and Services

Cite this

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Structure and Function of Chromatin Remodelling ATPases and their Dysfunction in Human Disease

Dundee Cancer Research UK Centre (Clinical Training Account)

Equipment

Data Analysis Group

Fingerprints Proteomics Facility

MRC PPU Reagents and Services

Cite this