Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach

Table 1 Host cell factors involved in the epigenetic maintenance of the covalently closed circular DNA minichromosome

	Category	Epigenetic effect	Effect on HBV	Ref.
Chromatin remodeling enzymes
Histone acetyltransferase p300/CBP	Writer	Increases H3K122a	Activation	Ananthanarayanan et al[99] and Tropberger et al[221]
P300/CBP-associated factor (PCAF)	Writer		Activation	Levrero et al[82] and Rivière et al[93]
Histone deacetylase 1 (HDAC1)	Eraser	Reduces acetylation of H3K9 and H3K27 with IFN	Inhibition	Pollicino et al[57] and Liu et al[98]
Sirtuin 1 and 3 (SIRT1/3)	Eraser	Reduces H3K9me3	Inhibition	Belloni et al[105] and Ren et al[114]
Enhancer of zeste homolog 2 (EZH2)	Writer	Increases H3K27ac and H3K27me3	Inhibition	Zhang et al[89]
Histone acetyltransferase 1 (HAT1)	Writer	Overexpression of HAT1 promotes acetylation of H3K27, H4K5 and H4K12	Activation	Yang et al[195]
Mixed lineage leukemia protein 3 (MLL3)	Writer	Increases H3K4me3	Activation	Tropberger et al[86] and Ananthanarayanan et al[99]
Protein arginine methyltransferase (PRMT)	Writer	PRMT5 interacts with HBc to increase H4R3me2s	Inhibition	Zhang et al[89]
Demethylases (KDMs)	Eraser	Increases H3K79me and function to transcriptional repression via SIRT1-mediated chromatin silencing	Inhibition	Kang et al[222]
Histone methyltransferase suppressor of variegation 3-9 homolog 1 (SUV39H1)	Writer	Increases H3K9me3	Inhibition	Peng and Karpen[223,224]
DNA methyltransferase (DNMTs)	Writer		Inhibition	Vivekanandan et al[81]
Methyl-CpG binding protein (MBPs)	Reader	Recruit chromatin remodeling and histone-modifying complexes to methylated sites resulting in histone methylation	Inhibition	Lopez-Serra and Esteller[94]
Cellular transcription factors
Activating transcription factor 2 (ATF 2)		Inhibition viral transcription	Inhibition	Choi et al[225]
cAMP response element binding protein (CREB)		Enhances transcription	Activation	Kim et al[226] and Song et al[227]
Nuclear factor 1 (NF1)	Reader		Activation	Ori et al[228] and Shaul et al[229]
Transcription factor Yin Yang 1 (YY1)			Inhibition	Belloni et al[199] and Nakanishi-Matsui et al[230]
Specificity protein 1 (SP1)	Reader		Activation	Raney and McLachlan[231], Raney et al[232] and Li and Ou[233]
Nuclear Transcription Factor Y (NF-Y)		Recruit enzymes that both methylate and acetylate histone proteins	Activation	Lu and Yen[234], Maity and de Crombrugghe[235] and Nardini et al[236]
Activator protein 1(AP-1)			Activation	Ren et al[111] and Choi et al[237]
TATA binding protein (TBP)	Reader		Activation	Bogomolski-Yahalom et al[238] and Chen et al[239]
Prospero-related homeobox protein (Prox1)			Inhibition	Qin et al[240]
Nuclear factor kappa-B (NF-κB)			Inhibition	Lin et al[241]
Histone-lysine N-methyltransferase SETDB1	Writer	In the absence of HBx, SETDB1 increases H3K9me2 and H3K9me3	Inhibition	Rivière et al[93]
Hepatocyte factors
Retinoid X receptors (RXRα)		Increases acetylation of histones H4 and H3 by recruiting p300 to cccDNA minichromosome	Activation	Zhang et al[89] and Nkongolo et al[242]
Small heterodimer partner (SHP)			Inhibition	Oropeza et al[243]
CAAT enhancer-binding protein α and ζ (C/EBP)		C/EBP in low concentrations; C/EBP in high concentrations	Activation; Inhibition	Raney and McLachlan[231] and López-Cabrera et al[244]
Hepatocyte nuclear factor 1 α and β (HNF1)		HNF1 and Oct 1 are essential co-activators of transcription. High HNF1 levels increase NF-κB expression and resulting in transcription inhibition	Activation and inhibition	Zhou and Yen[245], Zheng et al[246] and Lin et al[247]
Hepatocyte nuclear factor 3 α, β, and γ (HNF3)		Functions as a chromatin remodeler	Activation	Chen et al[248] and Li et al[249]
Hepatocyte nuclear factor 4 (HNF4)			Activation	Zheng et al[246], Cho et al[250] and Long et al[251]
Testicular orphan receptor 4 (TR4)			Inhibition	Lin et al[252]
Type I interferon (IFN-α)		Reduced acetylation of H3K9and H3K27	Inhibition	Pollicino et al[57], Liu et al[98] and Yuan et al[253]

cccDNA: Covalently closed circular DNA; NF-κB: nuclear factor-kappa B.