HDAC8 mutations in Cornelia de Lange Syndrome affect the cohesin acetylation cycle

Cornelia de Lange syndrome (CdLS) is a dominantly inherited congenital malformation disorder caused by mutations in the cohesin-loading protein NIPBL(1,2) for nearly 60% of individuals with classical CdLS(3-5) and in the core cohesin components SMC1A (~5%) and SMC3 (<1%) for a smaller fraction of probands(6,7). In humans, the multi-subunit complex cohesin is comprised of SMC1, SMC3, RAD21 and a STAG protein to form a ring structure proposed to encircle sister chromatids to mediate sister chromatid cohesion (SCC)(8) as well as play key roles in gene regulation(9). SMC3 is acetylated during S-phase to establish cohesiveness of chromatin-loaded cohesin(10-13) and in yeast, HOS1, a class I histone deacetylase, deacetylates SMC3 during anaphase(14-16). Here we report the identification of HDAC8 as the vertebrate SMC3 deacetylase as well as loss-of-function HDAC8 mutations in six CdLS probands. Loss of HDAC8 activity results in increased SMC3 acetylation (SMC3-ac) and inefficient dissolution of the “used” cohesin complex released from chromatin in both prophase and anaphase. While SMC3 with retained acetylation is loaded onto chromatin, ChIP-Seq analysis demonstrates decreased occupancy of cohesin localization sites that results in a consistent pattern of altered transcription seen in CdLS cell lines with either NIPBL or HDAC8 mutations.