Unraveling the relationship between histone methylation and nonalcoholic fatty liver disease

Table 1 Effect of histone methylation on glycolipid metabolism

Histone methylation	HMTs/HDMs	Mechanisms	Effects on glycolipid metabolism	Ref.
H3K4me3↑	MLL2/KMT2B	-	Regulation of glucose homeostasis	[20]
H3K4me3↑	MLL3/KMT2C	(+) KMT2C (2D) + PTIP→promoter (PPARγ) ←Transcript (C/EBPα); (+) KMT2C (2D) + PTIP→promoters (LPL, SREBF2, SCD1) ←Transcript (E2F1)	Lipid synthesis↑	[21,23,68]
	MLL4/KMT2D
H3K9me2/3↑	SUV39H1/KMT1A	(-) KMT1A (1D) →Transcript (C/EBPα) ←Enhancer (AP-2α); (-) KMT1D + PRDM16→promoter (HSD11B1)	Lipid synthesis↓	[27,28]
	EHMT1/KMT1D		Blood glucose↑
H3K9me2/3↑	EHMT2/KMT1C	(-) KMT1C→promoter (PPARγ) ←Transcript (C/EBPα); (+) KMT1C→Expression of HMGA1	Lipid synthesis↓	[30,31]
			Impaired insulin signal↓
H3K27me3↑	EZH2/KMT6A	(-) KMT6A→promoter (Mogat1) →MAG→DAG	Lipid synthesis↑	[42,45]
H3K79me1/2/↑	DOT1L	(+) DOT1L→Pathways of SREBP	Lipid synthesis↑	[49]
		(+) DOT1L→Brown and beige fat production and thermogenesis
H3K4me1/2↓	LSD1/KDM1A	(-) KDM1A + PRDM16→promoter (HSD11B1)	Lipid synthesis↑	[24,25]
			Blood glucose↓
H3K9me2/me3↓	JMJD2B/KDM4B	(+) KDM4B + PTIP→promoter (PPARγ) ←Transcript (C/EBPα)	Lipid synthesis↑	[32,33]
		(+) KDM4B + LXRα
H3k9me3↓	JMJD1C/KDM3C	(+) KDM3C + USF1→promoter; (Lipogenesis genes)	Lipid synthesis↑	[34]
H3K9me1/2↓	JHDM2a/KDM3A	(+) KDM3A (β-adrenaline) →PPRE←promoter (PPARγ + RXRα)	Lipid synthesis↓	[35,36]
H3K9me2↓	JHDM1D/KDM7A	(+) KDM7A→promoter (DGAT2)	Lipid synthesis↑	[37]
H3K27me2↓
H3K27me3↓	JMJD3/KDM6B	(+) KDM6B + islet1→promoter (SNAI1)	Lipid synthesis↓	[46]
H3K27me3↓	-	(+) promoter (LepRb) →slug-Epigenetic reediting-Leptin resistance axis	Leptin resistance↑	[48]
H3K36me2↑	NSD2	(-) NSD2→promoter (PPARγ)	Lipid synthesis↓	[47]
H3K27me3↓
H3K9me2/3↓	Phf2	(+) Phf2→ChREBP→promoter (FASN)	Lipid synthesis↑	[39,40]
			Fructose decomposition↑
H4K20me1↓	KDM7B	(-) promoter (RNA Pol II) →H4K20me1→Expression of glycolytic genes	Lipid synthesis↑	[55]
H4K20me3↓	-	(+) ChREBP→ChoRE + promoter (FASN) →H4K20me3→Expression of FASN	Lipid synthesis↑	[53]

HMTs: Histone methyltransferases; HDMs: Histone demethylases; Mogat1: Monoacylglycerol O-acyltransferase 1; DAG: Diacylglycerol; FASN: Fatty acid synthase; E2F1: E2F transcription factor 1; PTIP: Pax trans-activating structural domain-interacted protein; PPRE: The PPAR response element; Phf2: Plant homologous structural domain finger 2.

Table 2 Effect of histone methylation on inflammatory injury

Histone methylation	HMTs/HDMs	Mechanisms	Effects on Inflammatory Injury	Ref.
H3K4me3↑	SET7/9/KMT7	(+) SET7/9→promoter (TNF-α→Pro-inflammatory genes) ←NF-κB p65	Inflammatory reaction↑	[58]
H3K79me1/2/3↑	DOT1L	(+) DOT1L→Pathways of SREBP→ (-) Inflammatory expression of macrophages	Inflammatory reaction↓	[49]
H3R2me3↑	PRMT5	(+) PRMT5→promoter (OXR1A) →Growth Hormone	Oxidation stress↑	[64,65]
H3K27me3↓	JMJD3/KDM6B	In case of non-diabetic injury: (+) IFN-β→JAK1/3-STAT3→JMJD3→STING-TBK1/IRF3/IFN-α	In case of non-diabetic injury:Wound Recovery	[59-63]
		In case of diabetic injury: (-) IL-6→JAK1/3-STAT3→JMJD3→IFN-α; (+) IL-6→JAK1/3-STAT3→JMJD3→NF-κB	In case of diabetic injury:Inflammatory reaction↑

HMTs: Histone methyltransferases; HDMs: Histone demethylases; TNF-α: Tumor necrosis factor-α.

Table 3 Effect of histone methylation on hepatic fibrosis

Histone methylation	Functions	Effects on fibrosis	Ref.
H3K9me1/2/3↑	(Upstream) (-) Transcription initiation	Expression of PPARγ↓	[67,69,70]
		Hepatic Fibrosis↑
H3K27me1/2/3↑	(Downstream) (-) Transcriptional extensions	Expression of PPARγ↓	[67,69,70]
		Hepatic Fibrosis↑
H3K4me2/3↑	(The whole process) (+) Genes for fibrosis (TGF-β1, TIMP-1, α-SMA and Collagen type I)	Hepatic Fibrosis↑	[67,69,70]
H3K36me3↑

Table 4 Effect of histone methylation on carcinogenesis of fatty liver

Histone methylation	HMTs/HDMs	Functions	Effects on HCC	Ref.
H3K4me2↑	SETD7/KMT7	(+) Cell cycle G1 phase → S phase	↑	[72,73]
H3K9me1/2↑	G9a/KMT1C	(-) Expression of oncogenic factor RARRES3 and pro-apoptotic gene Bcl-G	↑	[85,86]
H3K9me3↑	SUV39H1/KMT1A	(+) Cell cycle G1 phase → S phase	↑	[87,88]
H3K27me3↑	EZH2/KMT6A	(+) Wnt/β-linked protein signaling pathways	↑	[91,92]
H4K20me1↑	SET8/KMT5A	(+) Cell cycle G1 phase → S phase	↑	[94,95]
H3K4me1/2/3↓	JARID1B/KDM5B	(+) Cell cycle G1 phase → S phase	↑	[75]
		(-) Oncogenic expression ← transcription factors (E2F1, P15 and P27)
H3K4me1/2↓	LSD1/LSD2/KDM1A	(+) Cell cycle G1 phase → S phase	↑	[77-79,90]
H3K9 me1/2↓		(-) H3K4me1/2↓→Inhibitor expression (β-linked protein signaling)
		(+) β-linked protein +TCF/LEF→Target gene expression (Oncogenic)
H3K9me1/2↓	JMJD1A/KDM3A	(+) PI3K/AP-1 pathway	↑	[89,90]
		(+) JAK2-STAT3 signaling pathways
		(+) Wnt/β-linked protein signaling pathways

HMTs: Histone methyltransferases; HDMs: Histone demethylases.