@article{f8c6e97e01554b2b8f527afbd533cfe0,
title = "Functional Interplay between Histone H2B ADP-Ribosylation and Phosphorylation Controls Adipogenesis",
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.",
keywords = "ADP-ribosylation, PARP-1, adipogenesis, differentiation, histones, phosphorylation, proliferation, proteomics, snoRNA",
author = "Dan Huang and Camacho, {Cristel V.} and Rohit Setlem and Ryu, {Keun Woo} and Balaji Parameswaran and Gupta, {Rana K.} and Kraus, {W. Lee}",
note = "Funding Information: The authors would like to thank the following: (1) members of the Kraus lab for continued input and feedback on this project; (2) Laura Banaszynski, Rebecca Gupte, Sridevi Challa, and Daeseok Kim for comments and feedback on this manuscript; (3) Tulip Nandu for assisting with the preliminary mass spectrometry data analysis; (4) Andrew Kelleher for assisting with the immunohistochemistry from mouse tissues; (5) Glen Liszczak for the nucleosomes used in the in vitro PARylation assays; (6) the University of Texas (UT) Southwestern Proteomics Core Facility under the direction of Andrew Lemoff; (7) the UT Southwestern Live Cell Imaging Core Facility under the direction of Kate Luby-Phelps; (8) the UT Southwestern Next Generation Sequencing Core under the direction of Ralf Kittler; and (9) the UT Southwestern Histo Pathology Core. This work was supported by a grant from the National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK069710) and funds from the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment to W.L.K. D.H. and W.L.K. conceived and developed this project. D.H. and W.L.K. designed the experiments and oversaw their execution. D.H. performed most of the experiments and analyzed the data, with assistance as follows: C.V.C. assisted with the mouse experiments, R.S. analyzed the RNA-seq data and the mass spectrometry data, R.K.G. developed the Mural Chaser mice and assisted K.W.R. with generating the Parp1 knockout lineage-tracing mouse model, and B.P. generated the asPARP-1 mass spectrometry samples from 3T3-L1 cells. All authors contributed to the design and analysis of the experiments that they did. D.H. prepared the initial drafts of the figures and text, which were edited and finalized by W.L.K. with input from the other authors. W.L.K. secured funding to support this project and provided intellectual support for all aspects of the work. 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. Funding Information: The authors would like to thank the following: (1) members of the Kraus lab for continued input and feedback on this project; (2) Laura Banaszynski, Rebecca Gupte, Sridevi Challa, and Daeseok Kim for comments and feedback on this manuscript; (3) Tulip Nandu for assisting with the preliminary mass spectrometry data analysis; (4) Andrew Kelleher for assisting with the immunohistochemistry from mouse tissues; (5) Glen Liszczak for the nucleosomes used in the in vitro PARylation assays; (6) the University of Texas (UT) Southwestern Proteomics Core Facility under the direction of Andrew Lemoff; (7) the UT Southwestern Live Cell Imaging Core Facility under the direction of Kate Luby-Phelps; (8) the UT Southwestern Next Generation Sequencing Core under the direction of Ralf Kittler; and (9) the UT Southwestern Histo Pathology Core. This work was supported by a grant from the National Institutes of Health ( NIH )/ National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK ) ( R01 DK069710 ) and funds from the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment to W.L.K. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = sep,
day = "17",
doi = "10.1016/j.molcel.2020.08.002",
language = "English (US)",
volume = "79",
pages = "934--949.e14",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}