Based on mouse studies, binding of EBF2 transcription factor to EBF sites within regulatory sequences of genes involved in brown/beige adipogenesis facilitates recruitment of PPARG to the nearby PPAREs (peroxisome proliferator activator response elements). In mouse brown and beige adipocyte lineages, PPARG enhances EBF2-stimulated transcription of the brown/beige adipogenesis target genes: PPARA, PRDM16, and UCP1 by directly binding to these gene loci (Rajakumari et al. 2013). PPARG binding to the UCP1 gene locus in mouse cells was also reported in Angueira et al. 2020, and Liu et al. 2020. PPARG also binds to the EBF2 target gene PPARGC1A (Pearson et al. 2019), which encodes brown/beige fat tissue-specific coactivator of PPARG, PGC1alpha, but PPARG-mediated induction of PPARGC1A gene expression has not been tested. PPARG also binds to the regulatory region of the CIDEA gene (inferred from mouse homologs in Brunmeir et al. 2016), a candidate EBF2 target, but PPARG-mediated induction of CIDEA has not been tested. PPARGC1A and CIDEA genes are annotated as candidate targets of PPARG in the context of prior EBF2-mediated regulation of brown/beige adipogenesis genes.

PPARG functions as a component of an obligate heterodimer with RXRA. The PPARG:RXRA heterodimer binds to target sequences in an inactive state, recruiting corepressors to target genes. Binding of ligands such as fatty acids to PPARG and retinoic acid to RXRA induces release of corepressors and recruitment of coactivators that can be tissue-specific, such as the brown/beige fat-specific coactivator PPARGC1A. The sequential activation of the PPARG:RXRA heterodimer, not shown in the context of this pathway, is reviewed in Jeninga et al. 2009. Although PPARG splicing isoform PPARG2 is implicated as the most relevant adipogenesis isoform, both PPARG1 and PPARG2 are expressed in the adipose tissue and therefore both isoforms are shown as members of the PAPRG set. As ABL1-mediated phosphorylation of PPARG2 in response to environmental stimuli increases protein stability (inferred from mouse homologs in Keshet et al. 2014), the phosphorylated form of PPARG2 is also included in the PPARG set. PPARG is known to recruit the histone methyltransferase complex MLL4 to its target genes, which is implicated in the establishment of super-enhancers at some of the EBF2 target genes, such as PRDM16 (inferred from mouse homologs in Lai et al. 2017).