Distinct roles of the JADE and BRPF scaffolding subunits of the acetyltransferase HBO1 complex.

The human acetyltransferase complex HBO1 is implicated in cancer and developmental diseases. Here, we report the chromatin association mechanisms for scaffolding subunits of the complex, the JADE and BRPF paralogs. Structural and biochemical studies reveal a distinct paralog-specific engagement of the PZP domains of JADE1/2/3 and BRPF1 with the nucleosome. We show that only JADE1's PZP domain possesses a strong intrinsic DNA binding activity and binds to an almost entire histone H3 tail, forming a tight complex with the nucleosome. In contrast, the BRPF1 PZP domain's association with the nucleosome is a thousand-fold weaker due to its inability to engage with the large portion of H3 tail and a weak binding to DNA. These results suggest that the JADE1 PZP domain can protect the H3 tail from being modified, but the BRPF1 PZP domain cannot, which could contribute to functional differences observed in the HBO1 complexes. We demonstrate non-redundant functions of the paralogs throughout embryonic development and embryonic stem cell pluripotency, during cardiac cell differentiation, and in differentiated liver cells. Our findings provide insights into the diverse mechanisms of action of the HBO1 complex and help to understand how the scaffolding subunits mediate its different cellular functions.