Reactome | Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes

Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes

Stable Identifier

R-HSA-9851695

Type

Pathway

Species

Homo sapiens

ReviewStatus

3/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes

Click the image above or here to open this pathway in the Pathway Browser

During adipogenesis, the KMT2D (MLL4) complex preferentially localizes to active enhancers, marked by the presence of mono- or dimethylated histone H3 lysine-4 (H3K4me1/2, residue K4 corresponds to residue K5 in nascent histone H3), acetylated H3 lysine-27 (H3K27ac), and the presence of RNA Pol II. KMT2D localizes to these active enhancers together with the adipogenic transcription factors CEBPB, CEBPA, and PPARG, and is especially enriched at high confidence enhancers that are both CEBP and PPARG positive (Lee et al. 2013). Single Kmt2c (Mll3) knockout in mouse brown preadipocytes led to a modest decrease of H3K4me1, while double Kmt2c;Kmt2d (Mll4) knockout led to a global decrease of H3K4me1/2 (Lee et al. 2013). Most MLL4-binding sites are marked by both H3K4me1 and H3K4me2 during adipogenesis (Lee et al. 2013). Double knockout of Kmt2c and Kmt2d in differentiating mouse adipocytes prevented increase in H3K4me1/2, H3K27ac, Mediator complex and RNA Pol II on adipogenic enhancers, specifically on Cebpa and Pparg gene loci (Lee et al. 2013). KMT2D-dependent deposition of H3K4me1/2 marks was also detected on some adipogenic promoters, but was less pronounced than on adipogenic enhancers (Lee et al. 2013). Deletion of Kmt2d significantly decreased expression of genes associated with Kmt2d+ adipogenic enhancers (Lee et al. 2013). The expression of KMT2C, the catalytic subunit of the MLL3 complex, is upregulated during brown adipocyte differentiation (Son et al. 2016).

Transgenic mice that express catalytically inactive form of Kmt2c (Lee, Saha et al. 2008; Lee, Lee et al. 2008) or that have a heterozygous loss of Kmt2d (Kim et al. 2016) are resistant to fatty liver formation induced by high-fat diet. Expression of a large portion of high-fat diet induced genes in mouse liver requires Kmt2d (Kim et al. 2016). Among the defined transcription factors that promote high-fat diet-induced hepatic steatosis (ChREBP, SREBP1c, LXRs, and PPARG), ChREBP and SREBP1c do not interact with KMT2C/D (Kim et al. 2016).

Gomisin N, a lignin isolated from magnolia-vine (Schisandra chinensis) was shown to inhibit, without cytotoxic effects, differentiation of mouse 3T3-L1 preadipocytes by inhibiting mitotic clonal expansion during early adipogenesis (Jang et al. 2017). Gomisin N treatment reduces KMT2D but not KMT2C mRNA levels, and also reduces the mRNA level of adipogenic transcription factors CEBPB, CEBPA, and PPARG, as well as their targets FABP4 (aP2) and FASN (FAS), inhibiting lipid accumulation and formation of lipid droplets, both in 3T3-L1 preadipocytes and in adipose tissue of mice on high fat diet. Gomisin N ameliorates hepatic steatosis in obese mice on high fat diet (Jang et al. 2017).

The epigenomic reader BRD4, essential for both white and brown adipose tissue development but dispensable for adipose tissue maintenance, is enriched on active enhancers during the initial stages of adipogenesis and on promoters that associate with enhancers at terminal stages of adipogenesis (Lee et al. 2017). More than 90% of Brd4 genomic binding sites lose Brd4 in mouse preadipocytes that are double knockout for Kmt2c and Kmt2d (Lee et al. 2017). The majority of Brd4-bound enhancers are co-occupied by Kmt2d, Ep300, Cebpa or Cebpb, and Pparg (Lee et al. 2017). Brd4 knockout does not affect binding of Cebpb and Kmt2d to adipogenesis target genes nor does it affect deposition of activating epigenetic marks, H3K4me1 and H3K27ac, at these genes, but it reduces binding of transcriptional machinery (e.g. Med1, Tbp, RNA Pol II, Cdk9) and mRNA synthesis (Lee et al. 2017). Brd2 and Brd3 may be able to partially compensate for the loss of Brd4 (Lee et al. 2017). Inhibition of Brd proteins by synthetic inhibitor JQ1 inhibits expression of Pparg targets Cepba, Fabp4 and Adipoq induced by rosiglitazone, a synthetic Pparg agonist (Lee et al. 2017). Brd4 was shown to physically associate with Cebpb (Lee et al. 2017). Conditional knockout mice in which Brd4 gene is deleted in progenitor cells of brown adipose tissue and muscle lineages die immediately after birth because of breathing impairment, exhibiting severe reduction in muscle mass and brown adipose tissue (Lee et al. 2017).

Based on mouse studies, at the onset of white and brown adipogenesis the accessory subunit of MLL3 and MLL4 complexes, PAGR1 (also known as PA1) is needed for induction of CEBPB and CEBPD transcription factors (Lee et al. 2020). Based on a study in immortalized mouse brown adipocytes, PAGR1 is recruited to the CEBPB gene promoter by activated CREB1, which is phosphorylated at serine residue S133 (p-S133-CREB1) (Lee et al. 2020). Based on a study in mouse white preadipocyte cell line 3T3-L1, PAGR1 is recruited to CEBPD gene promoter by ligand-activated glucocorticoid receptor (GR) (Lee et al. 2020).

Based on a study conducted using the mouse 3T3-L1 white preadipocyte cell line as a model system, dehydroleucodine, a sesquiterpene lactone isolated from Artemisia douglasiana (California mugwort) halts mitotic clonal expansion at the initiation of white adipogenesis (Abood et al. 2017). Dehydroleucodine decreases the phosphorylation of ERKs and AKT, as well as levels of CCNA, CCND, CDK2, and CDK4, while increasing the level of p27 (CDKN1B), resulting in G0/G1 cell cycle arrest of mouse white preadipocytes (Abood et al. 2017). Dehydroleucodine also downregulates JMJD2B and KMT2D, leading to downregulation of CEBPB and PPARG, respectively (Abood et al. 2017).

Expression of the histone 3 mutant H3.3 K4M in mouse brown preadipocytes impairs adipose tissue development, but when H3.3 K4M is expressed in already differentiated mouse brown adipocytes, the maintenance and thermogenic function of brown adipose tissue are not affected (Jang et al. 2019).

Literature References

PubMed ID	Title	Journal	Year
30335158	H3.3K4M destabilizes enhancer H3K4 methyltransferases MLL3/MLL4 and impairs adipose tissue development Park, YK, Lee, JE, Froimchuk, E, Jang, Y, Broun, A, Wang, C, Liu, C, Zhuang, L, Ge, K	Nucleic Acids Res	2019
28067305	Gomisin N inhibits adipogenesis and prevents high-fat diet-induced obesity Jung, MH, Kim, JH, Park, MH, Jang, MK, Yun, YR	Sci Rep	2017
27806304	Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARγ2 Kim, DH, Sandhu, J, Kwon, JS, Lee, JW, Lee, SK, Tontonoz, P, Lee, S, Kim, J	Cell Rep	2016
32601106	MLL3/MLL4-Associated PAGR1 Regulates Adipogenesis by Controlling Induction of C/EBPβ and C/EBPδ Ge, K, Deng, CX, Lee, JE, Cho, YW	Mol Cell Biol	2020
27157542	Methyltransferase and demethylase profiling studies during brown adipocyte differentiation Son, MJ, Park, A, Kim, WK, Lee, da S, Oh, KJ, Lee, SC, Bae, KH, Han, BS	BMB Rep	2016
19047629	Targeted inactivation of MLL3 histone H3-Lys-4 methyltransferase activity in the mouse reveals vital roles for MLL3 in adipogenesis Roeder, RG, Lee, J, Saha, PK, Lee, JW, Suh, Y, Chan, L, Lee, SK, Park, JY, Lee, S, Yang, QH	Proc Natl Acad Sci U S A	2008
29263365	Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis Ge, K, Ozato, K, Jang, Y, Park, S, Lee, JE, Waring, N, Park, YK, Lai, B, Dey, A, Peng, W	Nat Commun	2017
29663555	Dehydroleucodine inhibits mitotic clonal expansion during adipogenesis through cell cycle arrest Barbieri, MA, Abood, S, López, LA, Veisaga, ML	Phytother Res	2018
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, J, Lee, JW, Lee, SK, Lee, S	Mol Endocrinol	2008
24368734	H3K4 mono- and di-methyltransferase MLL4 is required for enhancer activation during cell differentiation Ge, K, Zhuang, L, Wang, C, Wang, L, Baldridge, A, Lee, JE, Feng, X, Sartorelli, V, Cho, YW, Xu, S, Peng, W	Elife	2013