NAD ⁺ Sensing by PARP7 Regulates the C/EBPβ-Dependent Transcription Program in Adipose Tissue In Vivo

We have identified PARP7, an NAD ⁺ -dependent mono(ADP-ribosyl) transferase, as a key regulator of the C/EBPβ-dependent proadipogenic transcription program. Moreover, PARP7 is required for efficient adipogenesis and downstream biological functions, including involution of the lactating mammary gland. PARP7 serves as a coregulator of C/EBPβ, and depletion of PARP7 causes a dramatic reduction in C/EBPβ binding across the genome. PARP7 functions as a sensor of nuclear NAD ⁺ levels to control gene expression. At the relatively high nuclear NAD ⁺ concentrations in undifferentiated preadipocytes, PARP7 is catalytically active for auto- mono(ADP-ribosyl)ation (autoMARylation). As nuclear NAD ⁺ concentrations decline post- differentiation, autoMARylation decreases dramatically. AutoMARylation promotes instability of PARP7 through an E3 ligase-ubiquitin-proteasome pathway mediated by the ADP-ribose (ADPR)-binding ubiquitin E3 ligases DTX2 and RNF114. Genetic depletion of PARP7 in mice promotes a dramatic reduction in a wide array of lipids in the mammary gland fat pads and milk from lactating females, as well as a significant decrease in nicotinamide mononucleotide (NMN), a key nutrient in mother's milk. The latter is due to reduced expression of Nampt , the gene encoding NAMPT, the enzyme that produces NMN, which is a direct transcriptional target of PARP7 and C/EBPβ. Collectively, our results extend the biology of PARP7 to adipogenesis and perinatal health. Moreover, our results describe the molecular events that regulate these downstream biological functions.