The AT-hook is an evolutionarily conserved auto-regulatory domain of SWI/SNF required for cell lineage priming

Dhurjhoti Saha, Solomon Hailu, Arjan Hada, Junwoo Lee, Jie Luo, Jeff A. Ranish, Yuan-chi Lin, Kyle Feola, Jim Persinger, Abhinav Jain, Bin Liu, Yue Lu, Payel Sen and Blaine Bartholomew ()
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Dhurjhoti Saha: Univ. of Texas MD Anderson Cancer Center
Solomon Hailu: Univ. of Texas MD Anderson Cancer Center
Arjan Hada: Univ. of Texas MD Anderson Cancer Center
Junwoo Lee: Univ. of Texas MD Anderson Cancer Center
Jie Luo: Institute for Systems Biology
Jeff A. Ranish: Institute for Systems Biology
Yuan-chi Lin: Univ. of Texas MD Anderson Cancer Center
Kyle Feola: Univ. of Texas MD Anderson Cancer Center
Jim Persinger: Univ. of Texas MD Anderson Cancer Center
Abhinav Jain: Univ. of Texas MD Anderson Cancer Center
Bin Liu: Univ. of Texas MD Anderson Cancer Center
Yue Lu: Univ. of Texas MD Anderson Cancer Center
Payel Sen: National Institute on Aging
Blaine Bartholomew: Univ. of Texas MD Anderson Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract The SWI/SNF ATP-dependent chromatin remodeler is a master regulator of the epigenome, controlling pluripotency and differentiation. Towards the C-terminus of the catalytic subunit of SWI/SNF is a motif called the AT-hook that is evolutionary conserved. The AT-hook is present in many chromatin modifiers and generally thought to help anchor them to DNA. We observe however that the AT-hook regulates the intrinsic DNA-stimulated ATPase activity aside from promoting SWI/SNF recruitment to DNA or nucleosomes by increasing the reaction velocity a factor of 13 with no accompanying change in substrate affinity (KM). The changes in ATP hydrolysis causes an equivalent change in nucleosome movement, confirming they are tightly coupled. The catalytic subunit’s AT-hook is required in vivo for SWI/SNF remodeling activity in yeast and mouse embryonic stem cells. The AT-hook in SWI/SNF is required for transcription regulation and activation of stage-specific enhancers critical in cell lineage priming. Similarly, growth assays suggest the AT-hook is required in yeast SWI/SNF for activation of genes involved in amino acid biosynthesis and metabolizing ethanol. Our findings highlight the importance of studying SWI/SNF attenuation versus eliminating the catalytic subunit or completely shutting down its enzymatic activity.

Date: 2023
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DOI: 10.1038/s41467-023-40386-8

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