1. Functional Interplay between Histone H2B ADP-Ribosylation and Phosphorylation Controls Adipogenesis.
- Author
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Huang D, Camacho CV, Setlem R, Ryu KW, Parameswaran B, Gupta RK, and Kraus WL
- Subjects
- Adenosine Diphosphate Ribose genetics, Adipocytes metabolism, Adipocytes pathology, Animals, Cell Line, DNA Damage genetics, Gene Expression Regulation, Developmental genetics, Mice, Phosphorylation genetics, RNA, Small Nucleolar genetics, ADP-Ribosylation genetics, Adipogenesis genetics, Histones genetics, Poly (ADP-Ribose) Polymerase-1 genetics
- Abstract
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., Competing Interests: Declaration of Interests W.L.K. is a founder and consultant for Ribon Therapeutics. He is also a co-holder of U.S. Patent 9,599,606 covering the ADP-ribose detection reagents used herein, which have been licensed to and are sold by EMD Millipore. All other authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)- Published
- 2020
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