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

Area of Science:

• Biochemistry
• Molecular Biology
• Metabolism

Background:

• Poly(ADP-ribose) polymerase 7 (PARP7) is a mono(ADP-ribosyl) transferase.
• Nuclear NAD+ levels fluctuate during adipocyte differentiation.
• C/EBPβ is a key transcription factor in adipogenesis.

Purpose of the Study:

• To identify regulators of C/EBPβ-dependent proadipogenic gene expression.
• To elucidate the role of PARP7 in adipogenesis.
• To understand the molecular mechanism linking PARP7 to C/EBPβ and adipogenesis.

Main Methods:

• Investigated PARP7 activity in relation to nuclear NAD+ concentrations.
• Utilized an E3 ligase-ubiquitin-proteasome pathway assay.
• Examined PARP7's coregulatory function with C/EBPβ.
• Performed genetic depletion of PARP7 in mice fed a high-fat diet.

Main Results:

• PARP7 acts as a nuclear NAD+ sensor, with auto-mono(ADP-ribosyl)ation (autoMARylation) decreasing as NAD+ levels fall during differentiation.
• AutoMARylation promotes PARP7 instability via DTX2 and RNF114-mediated ubiquitylation.
• Stabilized PARP7 enhances p300-mediated histone acetylation and C/EBPβ binding, promoting adipogenic gene expression.
• PARP7 depletion in mice led to reduced body weight, fat mass, and inhibited adipogenesis and lipid synthesis.

Conclusions:

• PARP7 is a critical regulator of adipogenesis.
• A novel PARP7-p300-H3K27ac-C/EBPβ pathway controls proadipogenic gene expression.
• PARP7 modulation impacts metabolic parameters, suggesting therapeutic potential.