The six unique histone deacetylase (HDAC) 1 complexes vary greatly in abundance and utilize distinct molecular assemblies

Histone deacetylase 1 and 2 (HDAC1/2) are highly related enzymes that that regulate histone acetylation levels in all cells, as catalytic and structural components of six unique multi-protein complexes: SIN3, NuRD, CoREST, MIDAC, MIER1 and RERE. Co-immunoprecipitation of HDAC1-Flag followed by mass-spectrometry revealed that 92% of the HDAC1 in mouse embryonic stem cells resides in 3 complexes, NuRD (49%), CoREST (28%) and SIN3 (15%). To delineate the function of these different biochemical entities we compared binary structures of the MTA1:HDAC1 and MIDAC:HDAC1 to identify conserved residues on the surface of HDAC1 that would potentially perturb one or more complexes. A single mutation, Y48E, disrupts binding to all complexes with the exception of SIN3. Remarkably, rescue experiments performed with HDAC1-Y48E in HDAC1/2 double-knockout cells, showed that retention of SIN3 binding alone is sufficient for cell viability. Gene expression and histone acetylation patterns were perturbed in both Y48E and a second mutant cell line, HDAC1-E63R, indicating that cells require a full repertoire of the HDAC1/2 complexes to regulate their transcriptome appropriately. Comparative analysis of SIN3/HDAC1 and MTA1/HDAC1 structures confirmed the differential modes of HDAC1 recruitment, with the surface including Y48 bound only by ELM2/SANT domain containing complexes. We provide novel molecular insights into the abundance, co-factors and assemblies of this crucial family of chromatin modifying machines.