Mll4,(Mll3)-ASCOM monomethylates nucleosomes at Pparg:Rxra-bound enhancers

Stable Identifier
R-MMU-9856368
Type
Reaction [transition]
Species
Mus musculus
Compartment
nucleoplasm
ReviewStatus
5/5
General
SVG | 
PNG
Low
Medium
High
 | PPTX  | SBGN
Mll4,(Mll3)-ASCOM monomethylates nucleosomes at Pparg:Rxra-bound enhancers
In mouse embryonic fibroblasts (MEFs), which only express Pparg1 but not Pparg2 isoform of Pparg, increased trimethylation of the Pparg1 proximal promoter at H3K4 (H3K4me3 mark of active chromatin), was dependent on the presence of Paxip1 (Ptip), an accessory subunit of Kmt2c (Mll3) and Kmt2d (Mll4) complexes (Cho et al. 2009).

Mouse brown preadipocytes expressing histone 3 mutant H3.3 K4M show severe defects in adipogenesis, along with reduced expression of adipogenesis markers Pparg, Cebpa, and Fabp4, decreased global levels of H3K4me1, H3K4me2, H3K4me3, and H3K27ac (Jang et al. 2019). Targeted knock-in of H3.3 K4M in somatic precursor cells of brown adipose tissue and skeletal muscle leads to death immediately after birth due to breathing malfunction, with affected newborn mice showing impaired development of brown adipose tissue and muscles (Jang et al. 2019). Expression of H3.3 K4M in mouse brown preadipocytes destabilizes endogenous KMT2C (MLL3) and KMT2D (MLL4) and their accessory subunit UTX (KDM6A), but does not affect KMT2A (MLL1), KMT2B (MLL2), SET1A, and SET1B (Jang et al. 2019).

In the mouse, Kmt2c/Kmt2d-dependent H3K4 methylation has been shown at the following Pparg target genes: Cd36 (Kim et al. 2016), Cebpa (Cho et al. 2009), Cidec (Kim et al. 2016), Fabp4 (Lee et al. 2008), Pparg (Cho et al. 2009), and Scd1 (Kim et al. 2016). Additional experimental details are provided in the inferred human reaction. While Kmt2c/Kmt2d-mediated H3K4 methylation of the nucleosomes at regulatory elements of Pparg target genes Acsl1, Acss3, Adipoq, Agpat2, Angptl4, Dgat2, Elovl5, Gpam, Lipe, Lpin1, Lpl, Mgll, Pdk4, Pex11a, Plin1, Plin2, Plin4, Pnpla2, Scd4, and Thrsp has not been reported, the expression of these genes, as well as the genes for which more direct evidence was available (Cd36, Cebpa, Cidec, Fabp4, Pparg, and Scd1), is severely reduced in differentiating mouse brown preadipocytes expressing histone H3.3 K4M mutant or Kmt2c and Kmt2d with deleted SET domains (Jang et al. 2019: RNA-seq, supplementary information).
Literature References
PubMed ID Title Journal Year
27806304 Critical Roles of the Histone Methyltransferase MLL4/KMT2D in Murine Hepatic Steatosis Directed by ABL1 and PPARĪ³2

Kim, DH, Kim, J, Kwon, JS, Sandhu, J, Tontonoz, P, Lee, SK, Lee, S, Lee, JW

Cell Rep 2016
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
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
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
Participants
Input
Output
Catalyst Activity

histone methyltransferase activity (H3-K4 specific) of Activated Pparg:Rxra:adipogenesis genes:nucleosomes:Mll4,(Mll3)-ASCOM [nucleoplasm]

Physical Entity
Activated Pparg:Rxra:adipogenesis genes:nucleosomes:Mll4,(Mll3)-ASCOM [nucleoplasm] (Mus musculus)
Activity
histone H3K4 methyltransferase activity (GO:0042800)
Orthologous Events
MLL4-ASCOM, (MLL3-ASCOM) complex monomethylates nucleosomes at PPARG:RXRA-bound enhancers (Homo sapiens)
Authored
Orlic-Milacic, M  (2023-12-18)
Reviewed
Khag, J  (2025-10-31)
Wang, SP  (2025-10-31)
Created
Orlic-Milacic, M  (2023-12-18)
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