PPARG2 transcription is stimulated by PPARG2:RXRA:MLL4,(MLL3)-ASCOM complex

Stable Identifier
R-HSA-9843116
Type
Reaction [omitted]
Species
Homo sapiens
Compartment
ReviewStatus
3/5
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Based on mouse studies, expression of the PPARG2 isoform of the PPARG gene, encoding Peroxisome proliferator-activated receptor gamma, a nuclear receptor transcription factor that is one of the master regulators of adipogenesis, is positively regulated in fat tissue by the PPARG:RXRA heterodimer, creating a positive feedback loop, and KMT2C (MLL3)/KMT2D (MLL4) histone methyltransferase complexes. Deletion of Paxip1 gene, encoding one of the mandatory accessory subunits of Mll3/Mll4 complexes, in mouse embryonic fibroblasts (MEFs) leads to over 10-fold decrease of expression of Pparg gene. Pparg1 is the only Pparg isoform expressed in MEFs. Pparg expression can be rescued by ectopic expression of Paxip1 (Cho et al. 2009). Deletion of Paxip1 in mouse brown preadipocytes almost completely prevents the induction of Pparg1, Pparg2, and Cebpa, but has little effect on the induction of their upstream transcription regulator Cebpb (Cho et al. 2009). In differentiating mouse brown preadipocytes, Paxip1 promotes recruitment of RNA Pol II to promoters of Pparg1 and Pparg2 isoforms (Cho et al. 2009). The expression of Pparg2 but not Pparg1 is induced by high fat diet in mouse liver in an Mll4-dependent manner (Kim et al. 2016). The overlapping Pparg, Kmt2d, and H3K4me1 ChIP-seq peaks are found around the Pparg2 promoter region, with each peak containing a conserved PPARE (peroxisome proliferator response element) (Kim et al. 2016). In a mouse hepatocyte cell line, transactivation of expression of Scd1, Cd36, and Cidec genes by Pparg2 but not Pparg1, in response to synthetic PPARG agonist rosiglitazone, is dependent on Kmt2d (Kim et al. 2016).

In mouse brown preadipocytes expressing histone 3 mutant H3.3 K4M the expression of Pparg is severely reduced (Jang et al. 2019). Deletion of SET domains of Kmt2c and Kmt2d in mouse brown preadipocytes prevents induction of Pparg during adipogenesis (Jang et al. 2019).
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