PRDM16 gene expression is stimulated by EBF2 and PPARG and repressed by ZNF423

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Reaction [omitted]
Homo sapiens
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PRDM16 gene encodes histone-lysine N-methyltransferase PRDM16, a transcriptional regulator that functions in the differentiation of brown adipose tissue. Based on mouse studies, expression of PRDM16 is directly regulated by the transcription factor EBF2, which binds to EBF binding elements in the PRDM16 gene (Rajakumari et al. 2013). EBF2-facilitated recruitment of the PPARG:RXRA transcription factor complex to the PPREs (peroxisome proliferator response elements) in the vicinity of EBF binding sites augments PRDM16 gene transcription synergistically with EBF2 (Rajakumari et al. 2013). PRDM16 mRNA level is significantly increased in the presence of mouse and human Blnc1 lncRNA that binds to and activates EBF2 transcriptional activity (Mi et al. 2017). During mouse brown fat differentiation, nearly all Ebf2+ precursor cells differentiate into Pparg+; Prdm16+ brown adipocytes (Wang et al. 2014). During differentiation of beige adipocytes in mouse inguinal white adipose tissue Ebf2 and Pparg synergistically upregulate Prdm16 mRNA levels (Stine et al. 2016). Fully differentiated brown adipocytes possess established super-enhancers at key cell type-specific genes, including Prdm16. In addition to the presence of EBF2 and PPARG, the PRDM16 super-enhancer is also bound by other adipogenesis transcription factors, such as CEBPB and CEBPA, as well as epigenetic regulators, such as MLL4 histone methyltransferase complex and CBP histone acetyltransferase, and exhibits epigenetic histone marks characteristic of active chromatin, such as MLL4-deposited H3K4me1 and CBP-deposited H3K27ac (inferred from mouse homologs in Lai et al. 2017). PRDM16 gene expression is negatively regulated by ZNF423-mediated inhibition of EBF2 transcriptional activity (inferred from mouse homologs in Shao et al. 2016; Shao et al. 2021).
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