Celiac disease: From genetics to epigenetics

Table 1 DNA methylation features in celiac disease

Predisposition to CeD	What	Result	Highlight in CeD
Allele-specific methylation (ASM)[24]		ASM in rs2762051 in DLEU1 gene	Linked to CeD phenotype
Rs906868 in LBH gene promoter[23]	Risk variant shared with RA	Disease-specific methylation	Different methylation in rs906868 can predispose to CeD or RA
			→ influence on Wnt signalling
Methylation in HLA region in CeD[30]	Specific patterns in epithelial and immune cells	Genotype-independent methylation (except for HLA-DPB2)	Methylation patterns in HLA region
			→ CeD predisposition
Methylation profiling in HLA-DQB1 and SLC17A3[32]	Bead-chip on saliva samples	Different methylation profiles, not confirmed in bigger cohort	Potential methylation-based screening
			Major validation needed
Opioid like-effect of gliadin[27]		Modulation of glutathione and DNA methylation	Predisposition to inflammation and oxidation
CeD pathogenesis
Methylation in NFkB-related genes[26]	NFkB pathway↑↑	Disruption of regulatory equilibrium	Co-methylation patterns typical of active CeD in NFkB pathway genes
Cell-specific methylation[30]		Epithelium → 43 DMP	Cell-specific methylation signature & gene expression in CeD vs controls
		Immune cells → 310 DMP
Different methylation of SB2H3, IL-21, cREL and TNFAIP3[31]	Epithelium and lamina propria - specificity	Correlation with pro-inflammatory(↑) and cell adhesion(↓) pathways	Methylation of SB2H3 → epithelium
			Methylation of IL21 → lamina propria
			Typical of CeD samples.
Tumor development
↑CpGs methylation[20]	Microsatellite instability	↓MLH1 expression	Typical in CeD-related small bowel adenocarcinoma
MLH1 deregulation[21]	APC gene hyper-methylation	Chromosomal aberrations/microsatellite instability	Defects in mismatch repair
			Typical in CeD-related small bowel adenocarcinomas
Microsatellite instability[22]	Typical CpGs methylator phenotype	Methylation profiling → phenotypical classification	Mesenchymal and immune phenotypes are common in CeD-related small bowel carcinoma

CeD: Celiac disease; ASM: Allele specific methylation; RA: Rheumatoid arthritis; DMP: Differentially methylated positions; CpGs: CpG islands.

Table 2 Celiac disease-relevant histone modifications

Modification		Focus	Result	Relevance in CeD
H3K27ac[36]	Activation and enhancing of transcription	Profiling in stimulated CTLs from CeD subjects	IL-15, IFNβ and IL-21 induce specific acetylation profiles in CTLs	Strong association between H3K27ac and gene expression IFNβ-induced
				IL-15-derived changes related to lncRNAs
H3K4me3[37]	Active transcription marker	Shared variants between CeD and RA	Similar histone enrichment in shared variants in simple cells	Different histone enrichment in disease-related specialized cells
H3K36me3[38]	Active transcription marker	SETD2 silenced in 32% of EATL	↓H3K36me3 → γδT cells expansion	Predisposition to lymphomagenesis
H3K27me3[39]	Gene silencing	PRC2–driven trimethylation	Villi → H3K27me3 on proliferation and differentiation genes	PRC2 methylation help maintenance of Wnt homeostasis → deregulation linked to CeD crypts hyperplasia
			Crypts → H3K27me3 on nutrient transport and cell killing genes

CeD: Celiac disease; CTLs: Cytotoxic T lymphocytes; LncRNAs: Long non-coding RNAs; ECM: Extracellular matrix; RA: Rheumatoid arthritis; EATL: Enteropathy associated T cell lymphoma; PRC2: Polycomb repressive complex 2.