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Increased ACTL6A Occupancy Within mSWI/SNF Chromatin Remodelers Drives Human Squamous Cell Carcinoma

Chiung-Ying Chang, Zohar Shipony, Ann Kuo, Kyle M. Loh, William J. Greenleaf, Gerald R. Crabtree
doi: https://doi.org/10.1101/2021.03.22.435873
Chiung-Ying Chang
1Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA
2Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA
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Zohar Shipony
3Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
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Ann Kuo
1Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA
2Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA
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Kyle M. Loh
4Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA
5Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
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William J. Greenleaf
3Department of Genetics, Stanford University School of Medicine, Stanford, California 94305, USA
6Department of Applied Physics, Stanford University, Stanford, California 94305, USA
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Gerald R. Crabtree
1Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA
2Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA
5Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA
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  • For correspondence: crabtree@stanford.edu
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Summary

Mammalian SWI/SNF (BAF) chromatin remodelers play dosage-sensitive roles in many human malignancies and neurologic disorders. The gene encoding the BAF subunit, ACTL6A, is amplified at an early stage in the development of squamous cell carcinomas (SCCs), but its oncogenic role remains unclear. Here we demonstrate that ACTL6A overexpression leads to its stoichiometric assembly into BAF complexes and drives its interaction and engagement with specific regulatory regions in the genome. In normal epithelial cells, ACTL6A was sub-stoichiometric to other BAF subunits. However, increased ACTL6A levels by ectopic expression or in SCC cells led to near-saturation of ACTL6A within BAF complexes. Increased ACTL6A occupancy enhanced polycomb opposition over the genome activating SCC genes and also enhanced the recruitment of transcription factor TEAD with its co-activator YAP, promoting their chromatin binding and enhancer accessibility. Both of these mechanisms appeared to be critical and function as a molecular AND gate for SCC initiation and maintenance, thereby explaining the specificity of the role of ACTL6A amplification in SCCs.

Highlights

  • ACTL6A occupancy within BAF complexes is sub-stoichiometric in normal epithelial cells.

  • SCC cells upregulate ACTL6A thus increasing ACTL6A assembly with BAF complexes.

  • Genome-wide chromatin profiling identifies ACTL6A-dependent regulatory regions.

  • Increasing ACTL6A incorporation enhances TEAD-YAP binding to BAF complexes.

  • ACTL6A overexpression counteracts polycomb-mediated repression at SCC signature genes.

Competing Interest Statement

G.R.C. is a founder and stockholder in Foghorn Therapeutics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 22, 2021.
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Increased ACTL6A Occupancy Within mSWI/SNF Chromatin Remodelers Drives Human Squamous Cell Carcinoma
Chiung-Ying Chang, Zohar Shipony, Ann Kuo, Kyle M. Loh, William J. Greenleaf, Gerald R. Crabtree
bioRxiv 2021.03.22.435873; doi: https://doi.org/10.1101/2021.03.22.435873
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Increased ACTL6A Occupancy Within mSWI/SNF Chromatin Remodelers Drives Human Squamous Cell Carcinoma
Chiung-Ying Chang, Zohar Shipony, Ann Kuo, Kyle M. Loh, William J. Greenleaf, Gerald R. Crabtree
bioRxiv 2021.03.22.435873; doi: https://doi.org/10.1101/2021.03.22.435873

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