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

Stokes, M. S.; Kim, Y. J.; Kim, Y.; Koul, S.; Chiu, S.-P.; Dasovich, M.; Zuniga, J.; Nandu, T.; Huang, D.; Mathews, T. P.; Solmonson, A.; Camacho, C. V.; Kraus, W. L.

doi:10.1101/2025.04.07.647692

bioRxiv · 10.1101/2025.04.07.647692

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

Stokes, M. S.·Kim, Y. J.·Kim, Y.·Koul, S.·Chiu, S.-P.·Dasovich, M.·Zuniga, J.·Nandu, T.·Huang, D.·Mathews, T. P.·Solmonson, A.·Camacho, C. V.·Kraus, W. L.

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Abstract

We have identified PARP7, an NAD+-dependent mono(ADP-ribosyl) transferase, as a key regulator of the C/EBP{beta}-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/EBP{beta}, and depletion of PARP7 causes a dramatic reduction in C/EBP{beta} 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 mothers 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/EBP{beta}. 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.

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Stokes, M. S., Kim, Y. J., Kim, Y., Koul, S., Chiu, S.-P., Dasovich, M., Zuniga, J., Nandu, T., Huang, D., Mathews, T. P., Solmonson, A., Camacho, C. V., Kraus, W. L.. 2025-04-08. NAD+ Sensing by PARP7 Regulates the C/EBPβ-Dependent Transcription Program in Adipose Tissue In Vivo. https://doi.org/10.1101/2025.04.07.647692

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