Epigenetic Aspects and Prospects in Autoimmune Hepatitis

Abstract

The observed risk of autoimmune hepatitis exceeds its genetic risk, and epigenetic factors that alter gene expression without changing nucleotide sequence may help explain the disparity. Key objectives of this review are to describe the epigenetic modifications that affect gene expression, discuss how they can affect autoimmune hepatitis, and indicate prospects for improved management. Multiple hypo-methylated genes have been described in the CD4⁺ and CD19⁺ T lymphocytes of patients with autoimmune hepatitis, and the circulating micro-ribonucleic acids, miR-21 and miR-122, have correlated with laboratory and histological features of liver inflammation. Both epigenetic agents have also correlated inversely with the stage of liver fibrosis. The reduced hepatic concentration of miR-122 in cirrhosis suggests that its deficiency may de-repress the pro-fibrotic prolyl-4-hydroxylase subunit alpha-1 gene. Conversely, miR-155 is over-expressed in the liver tissue of patients with autoimmune hepatitis, and it may signify active immune-mediated liver injury. Different epigenetic findings have been described in diverse autoimmune and non-autoimmune liver diseases, and these changes may have disease-specificity. They may also be responses to environmental cues or heritable adaptations that distinguish the diseases. Advances in epigenetic editing and methods for blocking micro-ribonucleic acids have improved opportunities to prove causality and develop site-specific, therapeutic interventions. In conclusion, the role of epigenetics in affecting the risk, clinical phenotype, and outcome of autoimmune hepatitis is under-evaluated. Full definition of the epigenome of autoimmune hepatitis promises to enhance understanding of pathogenic mechanisms and satisfy the unmet clinical need to improve therapy for refractory disease.

Keywords: autoimmune; chromatin modifications; epigenome; hepatitis; micro-ribonucleic acids; treatment.

Figure 1

Compacted and relaxed nucleosomes. Nucleosomes consist of two copies of four different histones (H) arranged as a histone octamer and double-stranded deoxyribonucleic acid (DNA) wrapped 1.65 times around each octamer. The entry and exit of the DNA from the nucleosome is secured by a linker histone (H1). Each core histone within the octamer has an N-terminal tail that can undergo post-translational modifications (PTMs) by the attachment of methyl (me), acetyl (ac), or phosphate (ph) groups to a particular amino acid in the histone tail. Lysine (K), serine (S), or arginine (R) are among other amino acids that can serve as attachment sites. The PTMs are orchestrated by various enzymes. Methylation of the histone tail is catalyzed by histone methyltransferase (HMT); acetylation is catalyzed by histone acetyltransferase (HAT); and phosphorylation is catalyzed by kinases. The PTMs can be reversed by enzymes that dissociate the appended groups from the amino acid residues. Acetylation is reversed by histone deacetylase (HDAC); methylation is reversed by histone demethylase (HDMT); and phosphorylation is reversed by phosphatases. Histone acetylation relaxes the nucleosome and promotes gene transcription, and histone de-acetylation compacts the nucleosome (heterochromatin) and represses gene transcription. Histone methylation can decrease (H3K9me3) or increase (H3K4me3) transcription depending on the methylation site and other variables. Histone phosphorylation can recruit other molecules, such as bromo-domain-containing protein 4 (BRD4), to the acetylation site (crosstalk) and promote gene transcription. DNA can be methylated by DNA methyltransferase (DNMT) or de-methylated by ten-eleven translocation methylcytosine dioxygenase (TET). DNA methylation is restricted to sites in which cytosine (C) is separated from guanine (G) by a phosphate (p). Methylated DNA is compacted and transcription factors have limited access to transcription sites. Ribonucleic acid polymerase (RNAP) is prevented (X) from copying the nucleotide sequence, and gene transcription is decreased. De-methylated DNA is relaxed; RNAP can open the double-stranded DNA; and gene transcription is increased.

Figure 2

Biogenesis and gene silencing action of micro-ribonucleic acids (miRNAs). MiRNAs are derived from the cell genome and processed within the nucleus by the ribonuclease III enzyme, Drosha, into pre-cursor miRNA. The precursor miRNA is transported to the cytoplasm by exportin 5 and processed further by the ribonuclease II enzyme, Dicer, to a miRNA duplex. The duplex is processed in a RNA-induced silencing complex (RISC), and the strand with less stable 5’ end is selected as the guide strand. The guide strand probes for complementary base pairs (bold lines) in the 3’ untranslated region (3’UTR) of messenger RNA (mRNA). The degree of complementarity between the guide strand and the mRNA determines if the mRNA will undergo cleavage by endonucleases (perfect complementarity) or translational repression (near perfect complementarity). Either fate induces post-transcriptional gene silencing. MiRNAs can leave the cell and enter the circulation by forming a plasma membrane-derived microvesicle or an endosomal-derived exosome.