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

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 the AT-hook however regulates the intrinsic DNA-stimulated ATPase activity without 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. Attenuation of SWI/SNF remodeling activity by the AT-hook is important in vivo for SWI/SNF regulation of chromatin structure and gene expression in yeast and mouse embryonic stem cells. The AT-hook in SWI/SNF is required for transcription regulation and activation of state-specific enhancers critical in cell lineage priming. Similarly, 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.