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CACUL1 reciprocally regulates SIRT1 and LSD1 to repress PPARγ and inhibit adipogenesis

ABSTRACT: Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation and is closely linked to the development of obesity. Despite a large progress on the transcriptional network of PPARγ, the epigenetic regulation associated with histone modification remains elusive. Here, we found that CDK2-associated cullin 1 (CACUL1), identified as a novel SIRT1 interacting protein, directly binds to PPARγ through the CoRNR box 2 and represses the transcription activity and adipogenic potential of PPARγ. Upon CACUL1 depletion, less SIRT1 and more LSD1 was recruited to the PPARγ-responsive gene promoter, leading to the increased histone H3K9 acetylation and decreased H3K9 methylation for PPARγ activation during adipogenesis of 3T3-L1 cells. These findings were reversed upon fasting or resveratrol treatment. Further, gene expression profiling using RNA-seq supported the repressive role of CACUL1 in PPARγ activation and fat accumulation. Finally, we confirmed the CACUL1 function in human adipose-derived stem cells. Overall, our data suggest that CACUL1 tightly regulates PPARγ signaling through the mutual opposition between SIRT1 and LSD1, providing additional insight into its use for anti-obesity treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE105055 | GEO | 2017/10/17

REPOSITORIES: GEO

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Mus musculus

Project description:CACUL1 reciprocally regulates SIRT1 and LSD1 for PPARγ repression and anti-adipogenesis

| PRJNA407013 | ENA

Mus musculus

Project description:CACUL1 reciprocally regulates SIRT1 and LSD1 for PPARγ repression and anti-adipogenesis

| PRJNA406857 | ENA

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