Rapid degradation of 6 class I HDAC complexes reveals minimal functional overlap between complexes

The class 1 HDACs 1, 2 and 3 form seven families of distinct large multiprotein complexes that regulate gene expression via deacetylation of lysines in histone tails. The degree of redundancy and functional overlap between complexes and their primary gene targets, remains unknown. We used CRISPR/Cas9 to independently tag HDAC complexes with FKBP12 ^F36V in HCT116 cells enabling rapid (<1 hr), PROTAC-mediated, degradation. RNA sequencing at 6 h reveals that together, the 4 major complexes (CoREST, NuRD, NCoR/SMRT and SIN3A) perturbed >50% of expressed genes. More than 60% of these are specific to an individual complex. Of genes regulated by more than one complex, approaching 50% are reciprocally regulated such that HDAC complexes act as antagonistic regulators. Homer analysis strongly suggests that the complexes are reliant on different transcription factors. This is the first study to identify the primary targets of individual HDAC complexes and directly compare the effects of rapid degradation on gene regulation in the same biological system.