Abstract
Abstract Adipogenesis is a complex and tightly regulated process that plays a vital role in multiple aspects of human health. The molecular mechanisms regulating adipogenesis are incompletely understood, although key facets of the signaling and regulatory pathways have been defined. ADP-ribosylation – the process whereby ADP-ribose moieties are covalently transferred from NAD+ to substrate proteins – has been shown to control multiple components of the adipogenic regulatory machinery, including the transcription factor C/EBPb. In order to explore the role of mono(ADP-ribosyl)transferases (MARTs) during adipogenesis, we used an siRNA-mediated knockdown screen in mouse 3T3-L1 preadipocytes to determine which MARTs are required for the differentiation of the preadipocytes into mature adipocytes. This screen identified PARP7 the primary candidate. Using a variety of cell-based and biochemical assays, we have identified key aspects of PARP7's involvement throughout adipogenesis. We observed dynamic localization of PARP7 during adipogenesis, moving from the nucleus in early adipogenesis to the cytosol during mid to late adipogenesis. The requirement for PARP7, as determined by knockdown, was most evident in early stages of adipogenesis. Knockdown of PARP7 was rescued by a PPAR g agonist, suggesting that PARP7 acts before the onset of the later stages of adipogenesis leading to mature adipocytes. Together, these findings led us to hypothesize that PARP7 plays a critical role in the nucleus during early adipogenesis. Preliminary data have revealed that PARP7 binds to C/EBPb, a key "first wave" transcription factor that drives adipogenesis, during a time when C/EBPb is poly(ADP-ribosyl)ated by PARP1 in the nucleus. Ongoing investigations are exploring: (1) the mechanisms by which PARP7 binds to C/EBPb; (2) the impact of PARP7 binding on C/EBPb stability; and (3) the biological outcomes of PARP7-C/EBPb interactions. Collectively, these studies provide an avenue to better understand the role of PARP7 in the regulation of adipogenesis. This work is supported by a grant from the NIH/NIDDK (R01 DK069710) and funds from the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment to W.L.K., and a predoctoral fellowship from the American Heart Association to M.S.S. Presentation: Monday, June 13, 2022 12:15 p.m. - 12:30 p.m.
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