NAD⁺ sensing by PARP7 regulates the C/EBPβ-dependent transcription program during adipogenesis

We identified poly(ADP-ribose) polymerase 7 (PARP7), a mono(ADP-ribosyl) transferase, as a regulator of C/EBPβ-dependent proadipogenic gene expression. PARP7 functions as a nuclear NAD⁺ sensor; at higher nuclear NAD⁺ concentrations in undifferentiated preadipocytes, PARP7 is catalytically active for auto-mono(ADP-ribosyl)ation (autoMARylation). As nuclear NAD⁺ concentrations decline upon differentiation, autoMARylation decreases dramatically. AutoMARylation promotes instability of PARP7 through an E3 ligase-ubiquitin-proteasome pathway mediated by the ubiquitin E3 ligases DTX2 and RNF114, which ubiquitylate MARylated PARP7. Stabilized PARP7 serves as a coregulator of C/EBPβ by stimulating p300-mediated histone H3 lysine 27 acetylation and the binding of C/EBPβ across the genome. Genetic depletion of PARP7 in mice promotes decreased body weight in mice fed a high-fat diet, reduced fat mass, inhibition of adipogenesis during mammary gland involution, and a reduction in lipid synthesis. Collectively, our results extend the biology of PARP7 to adipogenesis and elucidate the molecular mechanisms underlying a PARP7-p300-H3K27ac-C/EBPβ pathway for proadipogenic gene regulation.