Cancer-Associated Gain-of-Function Mutations Activate a SWI/SNF-Family Regulatory Hub

Our study strongly suggests that STH1 hub mutations partition into three categories, relative to WT Sth1: 1) Loss-of-function non-complementing mutations (low-moderate ATPase, no coupling), 2) Gain-of-function yet viable mutations (low-moderate ATPase, increased coupling), and 3) Gain-of-function inviable/dominant-lethal mutations (increased ATPase, moderate-WT coupling). To visualize the possible impact of gain-of-function human cancer-associated missense mutations on chromatin organization in vivo, in comparison to the two other mutation categories, we performed ATAC-seq experiments in S. cerevisiae, which provide accessibility profiles that are largely the inverse of nucleosomal occupancy profiles. Here, we reasoned that improvement in RSC nucleosome sliding would confer greater chromatin openness, perhaps genome-wide, due to the presence of RSC at most genes.