TABLE 1.

Summary of histone modifications and the corresponding mechanisms involved in CLD.

Diseases	PTM site	Corresponding effect	Writer/Eraser/inhibitor	References
ALD	H3K9ac	Activation of CPT1α, ADH I, PNPLA3	p300/HDAC/TSA	Park et al. (2012), Kirpich et al. (2013), Restrepo et al. (2017)
	H3K9/14/18/23ac and H3K27me3	—	—	Bardag-Gorce et al. (2009), Kriss et al. (2018)
	H3K4me2	Activation of ADH I and GST-Yc2	—	Pal-Bhadra et al. (2007)
	H3K9me	Repression of Lsdh and CYP2C11	—	Pal-Bhadra et al. (2007)
	H3S10/28ph	Activating H3K14 acetylation and inhibting acetylation of H3K9	p38 MAPK	Lee and Shukla (2007)
MAFLD	H3K9/K14/K18ac	Activation of TNFα, CCL2, Pol2 and NF-κB recruitment	HDAC1	Aagaard-Tillery et al. (2008), Mikula et al. (2014)
	H3K4/K9ac and H4K8/K16/K20ac and H3S10ph	Activation of FASN, SRE, ChoRE, PPARγ, SREBP-1c, ACLY	HAT (p300/CBP)	Du et al. (2017), Cai et al. (2018), Chung et al. (2019), Rohrbach et al. (2019)
	H3K27ac	Activation of Scd1, Cyp4a14, PPAR, C/EBP, NF4, and SREBP	---	Siersbæk et al. (2017), Becares et al. (2019)
	H3K9me2/3 demethylation	Activation of LXRE and ERO1-α, increasing hepatic LXRα-dependent lipogenic genes	JMJD2B	Li et al. (2012), Kim et al. (2020)
	H3K9me2 demethylation	Activation of ChREBP, PPARγ, Nrf2, or HIF1α, and protecting the liver from pathogenic lipids and ROS accumulation	KDM (Phf2)	Bricambert et al. (2018)
	H3K4me	Activating steatotic target genes of PPARγ2 and TNFα-induced inflammatory genes	MLL4/KMT2D/SET7/9	Li et al. (2008), Kim et al. (2016)
Viral hepatitis	H2A.Zac and H3K9ac deacetylation	Changes in hepatocyte chromatin structure	Sirtuin deacetylase	Jenke et al. (2014)
	H4 deacetylation and decreased H2AXph	Changing hepatocarcinogenesis-associated genes expression and impeding DNA damage repair	PP2A	Duong et al. (2010)
	H3K27/H4K5/H4K12ac on cccDNA	Promoting HBV replication and cccDNA accumulation	HAT1/HDAC I	Pollicino et al. (2006), Luo et al. (2013), Koumbi et al. (2016), Yang et al. (2019)
	H3K9/K27 deacetylation in cccDNA	Required for cccDNA transcription	HDAC	Liu et al. (2013)
	H4 demethylation	Changing expression of genes important for hepatocarcinogenesis	PRMT1	Duong et al. (2010)
	H3K27me3 demethylation	—	—	Hlady et al. (2021)
	H3K9me and demethylation of H3K4me3 in cccDNA	Recruitment of HP1 and consequently repressed viral gene expression	SETDB1, SET 1A/LSD1	Rivière et al. (2015), Alarcon et al. (2016)
	H4R3me2s on cccDNA	Repressing cccDNA transcription	PRMT5	Zhang et al. (2017)
	Decreased H3S10ph	Downregulation of NF-κB and COX-2 transcription	AURKB	Madejón et al. (2015)
	Decreased H3ph in cccDNA	Reducing replication, transcription, and antigen secretion of HBV	—	Luo et al. (2013)
Autoimmune liver disease	H4 acetylation	Activation of LIGHT, CD40L, IL-17 and INF-γ, increasing T cell proliferation, interferon production	—	Hu et al. (2011)
	H4 deacetylation	Activation of HDAC7A, APO2, and TRAIL, reducing activities of NF-κB and AP-1	—	Hu et al. (2011)
	H3K27ac	Activation of anti-apoptotic BCL-xL during cholangiocyte senescence	p300	O’hara et al. (2019)
	H3K4me3	Activation of CDKN2A during cholangiocyte senescence	—	O’hara et al. (2017)
DILI	H3K9ac	Activation of stress-related genes	—	Sinha et al. (2016)
	H3K9me3	Repression of stress and metabolic-associated genes	—	Sinha et al. (2016)
	H3S10ph	An critical role in liver regeneration after injury	—	Sinha et al. (2016)
Liver fibrosis/Cirrhosis	H3K9ac	Activation of TNFα and EGFR, increases MYC and cyclin D1, activating HSCs	—	Yang et al. (2014), Sarr et al. (2016), Zheng et al. (2020)
	H3K27ac	Activation of AP-1, Col1α1/2, TEAD, IGFBP-3 and NF-κB, and activating HSCs, activation of TNFα-induced CCL2 transcription in LSECs	p300/BRD4	Liu et al. (2020), Yaqoob et al. (2020) Gao et al. (2021)
	H4 deacetylation/acetylation	Repression of PPARγ gene during cirrhosis/inhibiting HSCs proliferation and collagen deposition	HDAC3/HDACi (VPA)	(Mannaerts et al., 2010; Rodríguez-Aguilera et al., 2018)
	H3K4me/me3	Activation of αSMA, TIMP, Col1 and TGF-β1/increasing HIF-1 nuclear transport, autophagosome formation, and activation of HSC	ASH1	Perugorria et al. (2012), Hong et al. (2018)
	Increased H3K4me1/2/3, reduced H3K9me2/3	TGF-β overexpression	KMT 7 (SET7/9)	Sheen-Chen et al. (2014)
	H3K27me3	Repression of PPARγ, CFTR, enhancing autophagy	Methyltransferas EZH2	Zeybel et al. (2012), Yang et al. (2018)
	H2BK120ub	Repression of IL-6, TNF-α, VEGFA, α-SMA and Col1α1	RNF20	Chen et al. (2021)
	H2A deubiquitination	Apoptosis of fibroblasts and liver tissue	BAP1	He et al. (2019)

Abbreviations: Alcohol dehydrogenase I (ADHI); Alpha-smooth muscle actin (αSMA); Angiopoietin-like 4 (Angtpl4); ATP-citrate lyase (ACLY); Aurora B kinase (AURKB); Carbohydrate-responsive elements (ChoRE); Carbohydrate-responsive element-binding protein (ChREBP); Carnitine palmitoyltransferase-1alpha (CPT1alpha); Chemokine C-C ligand 2 (CCL2); Cyclin-dependent kinase inhibitor 2A (CDKN2A); Cystic fibrosis transmembrane conductance regulator (CFTR); Cytochrome P450, family 4, subfamily a, polypeptide 14 (Cyp4a14); Fatty acid synthase (FASN); Fibroblast growth factor 21 (Fgf21); Glutathione-S-transferase subunit Yc2 (GST Yc2); HDAC3 inhibitor Trichostatin A (TSA); Heterochromatin protein 1 factor (HP1); Histone lysine demethylase-1 (LSD1); Homocysteine (Hcy); Hypoxia-inducible factor-1 (HIF-1); Insulin receptor substrate 2 (Irs2); Insulin-like growth factor binding protein-3 (IGFBP-3); Lactate dehydrogenase (LDH). Nuclear factor, interleukin 3 regulated (Nfil3); Nuclear factor-κB (NF-κB); Patatin-like phospholipase domain-containing 3 (PNPLA3); Peroxisome proliferator activated receptor (PPAR); Plant Homeodomain Finger 2 (Phf2); Polymerase 2 RNA (POL2); Protein phosphatase 2A (PP2A); Pyruvate dehydrogenase complex (PDHC); Sterol regulatory elements (SRE); Sterol-regulatory element binding protein- (SREBP); Synectin (GIPC); Tissue inhibitor of metalloproteinase-1 (TIMP1); Transforming growth factor (TGF-β) Transcription factor NF-E2-related factor 2 (Nrf2); Tumor necrosis factor alpha (TNFα); ring finger protein 20 (RNF20); BRCA1-Associated Protein 1 (BAP1);