Reactome | MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis

MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis

Stable Identifier

R-HSA-9841922

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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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)

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MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis

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The ligand-activated complex of a master transcription regulator of adipogenesis, nuclear receptor PPARG, and its partner, nuclear receptor RXRA, recruits MLL3 and MLL4 complexes to target gene loci, leading to establishment of activating epigenetic chromatin marks. The existing experimental evidence implies that MLL3-ASCOM and MLL4-ASCOM complexes are recruited to PPARG:RXRA-target loci, as described below.

PPARG isoform PPARG2-positive adipocyte nuclei isolated from visceral adipose tissue show significantly higher expression level of KMT2C, the catalytic subunit of the MLL3 complex, and PAXIP1, a cofactor of MLL3 and KMT2D (MLL4) complexes, than PPARG2-negative nuclei (Yu et al. 2016). Based on mouse studies, PAXIP1 (PTIP), an accessory subunit of MLL3 and MLL4 complexes, is required for adipogenesis in mouse embryonic fibroblasts (MEFs) and primary preadipocytes. PAXIP1-deficient MEFs show significant defects in both PPARG- and CEBPA-stimulated adipogenesis (Cho et al. 2009). Knockout of Paxip1 gene in brown adipose tissue (BAT) leads to significant decrease of BAT in knockout mice, and a significant decrease of expression of markers shared between white adipose tissue and BAT, such as Pparg, Cebpa, and Fabp4, as well as BAT-specific/prevalent markers Prdm16, Cidea, Mpzl2 (Eva1), Ntrk3, Ucp1, Ppargc1a (Pgc1a), Cox5b and Cox8b (Cho et al. 2009). Paxip1 BAT knockout mice are cold intolerant, with impaired cold-mediated induction of genes involved in fatty acid catabolism, such as Cpt1a, Lpl, and Mlycd (Mcd) (Cho et al. 2009).

In prostate cancer, KMT2D and PPARG are overexpressed at the protein level relative to the normal tissue (Zhai et al. 2022). KMT2D knockdown significantly reduces the lipid droplet content in prostate cancer cell lines (Zhai et al. 2022). In prostate cancer tumors, KMT2D mRNA expression significantly correlates with mRNA expression of lipid metabolism genes FASN, ACC, SCD, and ACLY (Zhai et al. 2022). KMT2D knockdown in prostate cancer cell lines leads to significant decrease in the mRNA levels of ACC, ACLY, and FASN (Zhai et al. 2022). Stimulation of PPARG by the synthetic agonist rosiglitazone stimulates lipid synthesis in prostate cancer cell lines, but the effect of rosiglitazone is diminished upon KMT2D knockdown (Zhai et al. 2022).

In addition to regulating genes involved in lipid metabolism, the PPARG:RXRA complex (Nielsen et al. 2008) and MLL3/MLL4 complexes (Jang et al. 2019: supplementary information) may also regulate expression of some of the genes involved in glucose metabolism and the tricarboxylic acid (TCA) cycle.

Hepatic steatosis represents the synthesis and accumulation of triglycerides in hepatocytes which can, if prolonged, lead to the development of non-alcoholic fatty liver disease (NAFLD) that can progress to non-alcoholic steatohepatitis (NASH), ultimately resulting in liver cirrhosis (Hardy et al. 2016). Like Kmt2c (Mll3) delta/delta mice, which express catalytically inactive Kmt2c (Lee, Saha et al. 2008; Lee S., Lee J. et al. 2008), Kmt2d (Mll4)+/- mice, with deletion of one allele of Kmt2d, are resistant to high fat diet-induced hepatic steatosis, with Kmt2d+/- livers accumulating much less fat relative to wild type littermate controls in response to high fat diet feeding (Kim et al. 2016). Bulk transcriptomic analysis of Kmt2d+/- mouse livers shows that the expression of a large portion of high fat diet controlled genes requires Kmt2d (Kim et al. 2016). Among the defined hepatic steatotic transcription factors, which include MLXIPL (ChREBP), SREBF1 (SREBP1) isoform SREBP1c (SREBP 1C), the liver X receptors (LXRs) – NR1H3 (LXRA) and NR1H2 (LXRB), and PPARG, KMT2D has been reported to associate with LXRs (Lee S., Lee J. et al. 2008) and PPARG (Lee, Saha et al. 2008). No association between mouse orthologs of KMT2D and MLXIPL or SREBP1c could be detected (Kim et al. 2016).

Literature References

PubMed ID	Title	Journal	Year
18372346	Activating signal cointegrator-2 is an essential adaptor to recruit histone H3 lysine 4 methyltransferases MLL3 and MLL4 to the liver X receptors Lee, S, Lee, J, Lee, SK, Lee, JW	Mol Endocrinol	2008
19047629	Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis Lee, J, Saha, PK, Yang, QH, Lee, S, Park, JY, Suh, Y, Lee, SK, Chan, L, Roeder, RG, Lee, JW	Proc Natl Acad Sci U S A	2008
19583951	Histone methylation regulator PTIP is required for PPARgamma and C/EBPalpha expression and adipogenesis Cho, YW, Hong, S, Jin, Q, Wang, L, Lee, JE, Gavrilova, O, Ge, K	Cell Metab	2009
26980160	Nonalcoholic Fatty Liver Disease: Pathogenesis and Disease Spectrum Hardy, T, Oakley, F, Anstee, QM, Day, CP	Annu Rev Pathol	2016
36093518	Histone methyltransferase KMT2D mediated lipid metabolism via peroxisome proliferator-activated receptor gamma in prostate cancer Zhai, Q, Luo, M, Zhang, Y, Zhang, W, Wu, C, Lv, S, Wei, Q	Transl Cancer Res	2022
27171244	Subsets of Visceral Adipose Tissue Nuclei with Distinct Levels of 5-Hydroxymethylcytosine Yu, P, Ji, L, Lee, KJ, Yu, M, He, C, Ambati, S, McKinney, EC, Jackson, C, Baile, CA, Schmitz, RJ, Meagher, RB	PLoS One	2016
18981474	Genome-wide profiling of PPARgamma:RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis Nielsen, R, Pedersen, TA, Hagenbeek, D, Moulos, P, Siersbaek, R, Megens, E, Denissov, S, Børgesen, M, Francoijs, KJ, Mandrup, S, Stunnenberg, HG	Genes Dev	2008
30335158	H3.3K4M destabilizes enhancer H3K4 methyltransferases MLL3/MLL4 and impairs adipose tissue development Jang, Y, Broun, A, Wang, C, Park, YK, Zhuang, L, Lee, JE, Froimchuk, E, Liu, C, Ge, K	Nucleic Acids Res	2019
27806304	Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2 Kim, DH, Kim, J, Kwon, JS, Sandhu, J, Tontonoz, P, Lee, SK, Lee, S, Lee, JW	Cell Rep	2016