Reactome | Unliganded PPARG:RXRA heterodimer recruits corepressors to target gene loci

Unliganded PPARG:RXRA heterodimer recruits corepressors to target gene loci

Stable Identifier

R-HSA-9843115

Type

Reaction [transition]

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

3/5

Locations in the PathwayBrowser

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Gene expression (Transcription) (Homo sapiens)

- Epigenetic regulation of gene expression (Homo sapiens)
  - Epigenetic regulation by WDR5-containing histone modifying complexes (Homo sapiens)
    - Epigenetic regulation of gene expression by MLL3 and MLL4 complexes (Homo sapiens)
      - Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes (Homo sapiens)
        
        MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis (Homo sapiens)
        
        Unliganded PPARG:RXRA heterodimer recruits corepressors to target gene loci (Homo sapiens)

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Unliganded PPARG:RXRA heterodimer recruits corepressors to target gene loci

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When activating ligands of PPARG are absent, PPARG:RXRA recruits the NCoR/SMRT corepressor complexes (reviewed in Farmer 2006, Cohen 2006, Jeninga et al. 2009). Based on studies in mouse adipocytes, yeast-two-hybrid studies using recombinant mouse proteins, and in vitro studies with mouse reagents, the NCoR/SMRT subunits NCOR2 (SMRT) (Lavinsky et al. 1998, Guan et al. 2005, Allen et al. 2006), NCOR1 (NCoR) (Krogsdam et al. 2002, Guan et al. 2005, Allen et al. 2006), and HDAC3 (Fajas et al. 2002, Guan et al. 2005) were shown to be recruited to unliganded PPARG:RXRA to maintain the target genes in an inactive state. The recruitment of NCoR/SMRT complexes may differ between different PPARG target genes and developmental stages in adipocytes and depend on the chromatin state (Guan et al. 2005). Based on studies in mouse adipocytes, downregulation of NCOR1 or NCOR2 leads to increased expression of PPARG target genes in the presence of PPARG ligands (Yu et al. 2005). Based on a mouse study, PPARG may have a higher affinity for NCOR2 than NCOR1, which may be further increased in the presence of activated ERKs (MAPK1/3) (Lavinsky et al. 1998). The recombinant human PPARG:RXRA complex bound to PPAR response element (PPARE)-containing oligonucleotides binds both mouse Ncor1 and Ncor2 (Gurnell et al. 2000). Human PPARG2 interacts with NCOR1, and the interaction is abolished in the presence of PPARG agonists (Oberfield et al. 1999). No significant interaction was detected between human PPARG2 and NCOR2 (Oberfield et al. 1999). In the study by Fujimura et al. 2005, both human NCOR1 and NCOR2 interacted with human PPARG2 in the absence of ligand, and were released from PPARG2 in the presence of ligand. While both PPARG1:RXRA and PPARG2:RXRA complexes interact with both NCOR1 and NCOR2 in vitro, NCOR1 and NCOR2 may not be recruited to every PPARG:RXRA target promoter (Zamir et al. 1997). Recombinant mouse Pparg and Hdac1 were reported to interact in vitro, but the in vivo significance of this interaction, if any, is unknown (Yoo et al. 2006). While Hdac1 levels decrease during differentiation of mouse adipocytes, levels of Hdac3, an NCoR/SMRT component, are unaffected (Yoo et al. 2006). Hypophosphorylated RB1 was reported to promote association of HDAC3 with the ligand-bound PPARG in human osteosarcoma cell lines (Fajas et al. 2002). Based on studies in mouse preadipocyte cell line 3T3-L1, RB1 may tune the association and release of corepressors and thus the transcriptional activity of the PPARG:RXRA complex with mitotic clonal expansion and mitotic exit of differentiating adipocytes (Fajas et al. 2002). Based on studies in mice, NAD-dependent protein deacetylase SIRT1 associates with PPARG and NCOR/SMRT at PPARG-target genes during fasting and contributes to repression of PPARG-mediated transcription (Picard et al. 2004). Using human embryonic lung diploid fibroblast cell lines WI-38 and 2BS, SIRT1 was shown to deacetylate PPARG, which decreases PPARG transcriptional activity (Han et al. 2010). PPARG can form a complex with SIRT1 on the SIRT1 promoter, acting to decrease SIRT1 gene transcription, thus creating a negative feedback loop (Han et al. 2010). Transcriptional levels of SIRT1 decline in senescent WI-38 cells and in lung, fat, and heart tissues from senescent mice (Han et al. 2010). PPARG levels remain constant in young and senescent cells, but the transcriptional activity of PPARG increases in senescent cells (Han et al. 2010). Expression of Zbtb7c, a putative transcriptional repressor of Sirt1, is increased in the liver and white adipose tissues of aging or high-fat diet-fed mice (Choi et al. 2021). CDK5-mediated phosphorylation of PPARG2 on serine residue S273 (corresponds to S245 in PPARG1) was reported to increase the affinity of PPARG2 for the corepressor NCOR2 (SMRT), while decreasing the affinity for NCOR1 (NCoR) (Dias et al. 2020: human recombinant PPARG2 was used with human recombinant NCOR2 and mouse recombinant Ncor1).

Literature References

PubMed ID	Title	Journal	Year
16314690	FK614, a novel peroxisome proliferator-activated receptor gamma modulator, induces differential transactivation through a unique ligand-specific interaction with transcriptional coactivators Sakuma, H, Kimura, C, Mutoh, S, Aramori, I, Konishi, S, Oe, T, Hosogai, N, Fujimura, T	J Pharmacol Sci	2005
33329381	PPARγ S273 Phosphorylation Modifies the Dynamics of Coregulator Proteins Recruitment Figueira, ACM, Le Maire, A, Dias, MMG, Silveira, LR, de Oliveira, AG, Batista, FAH, Torres, FR, Tittanegro, TH, Filho, HVR	Front Endocrinol (Lausanne)	2020
12479814	The retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte differentiation Debril, MB, Egler, V, Hansen, J, Miard, S, Kristiansen, K, Reiter, R, Fajas, L, Auwerx, J	Dev Cell	2002
10339548	A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation Mohr, CP, Collins, JL, Kliewer, SA, Lehmann, JM, Blanchard, SG, Cooper, JP, Plunket, K, Moore, LB, Hull-Ryde, EA, Milburn, MV, Goreham, DM, Oberfield, JL, Miller, AB, Holmes, CP, Willson, TM, Cobb, JE, Lenhard, JM, Parks, DJ	Proc Natl Acad Sci U S A	1999
20660480	SIRT1 is regulated by a PPAR{γ}-SIRT1 negative feedback loop associated with senescence Zhou, R, Wang, P, Tong, T, Han, L, Niu, J, McNutt, MA	Nucleic Acids Res	2010