Functional Interplay between Histone H2B ADP-Ribosylation and Phosphorylation Controls Adipogenesis

Although ADP-ribosylation of histones by PARP-1 has been linked to genotoxic stress responses, its role in physiological processes and gene expression has remained elusive. We found that NAD+-dependent ADP-ribosylation of histone H2B-Glu35 by small nucleolar RNA (snoRNA)-activated PARP-1 inhibits AMP kinase-mediated phosphorylation of adjacent H2B-Ser36, which is required for the proadipogenic gene expression program. The activity of PARP-1 on H2B requires NMNAT-1, a nuclear NAD+ synthase, which directs PARP-1 catalytic activity to Glu and Asp residues. ADP-ribosylation of Glu35 and the subsequent reduction of H2B-Ser36 phosphorylation inhibits the differentiation of adipocyte precursors in cultured cells. Parp1 knockout in preadipocytes in a mouse lineage-tracing genetic model increases adipogenesis, leading to obesity. Collectively, our results demonstrate a functional interplay between H2B-Glu35 ADP-ribosylation and H2B-Ser36 phosphorylation that controls adipogenesis. [Display omitted] •Glu35 on histone H2B is a key site of PARylation and regulation during adipogenesis•NMNAT-1 promotes snoRNA-activated PARP-1 Glu/Asp PARylation activity•H2B-Glu35 PARylation inhibits H2B-Ser36 phosphorylation to control adipogenesis•PARP-1 controls adipogenesis and body weight by regulating adipocyte precursors Huang et al. show that the nuclear NAD+ synthase, NMNAT-1, directs PARP-1 catalytic activity to Glu and Asp residues on histones. Physiological ADP-ribosylation of histone H2B-Glu35 by snoRNA-activated PARP-1 with NMNAT-1 inhibits AMPK-mediated phosphorylation of adjacent H2B-Ser36, which is required for proadipogenic gene expression and fat metabolism in vivo.