Mechanism and Therapeutic Opportunities of Histone Modifications in Chronic Liver Disease

Abstract

Chronic liver disease (CLD) represents a global health problem, accounting for the heavy burden of disability and increased health care utilization. Epigenome alterations play an important role in the occurrence and progression of CLD. Histone modifications, which include acetylation, methylation, and phosphorylation, represent an essential part of epigenetic modifications that affect the transcriptional activity of genes. Different from genetic mutations, histone modifications are plastic and reversible. They can be modulated pharmacologically without changing the DNA sequence. Thus, there might be chances to establish interventional solutions by targeting histone modifications to reverse CLD. Here we summarized the roles of histone modifications in the context of alcoholic liver disease (ALD), metabolic associated fatty liver disease (MAFLD), viral hepatitis, autoimmune liver disease, drug-induced liver injury (DILI), and liver fibrosis or cirrhosis. The potential targets of histone modifications for translation into therapeutics were also investigated. In prospect, high efficacy and low toxicity drugs that are selectively targeting histone modifications are required to completely reverse CLD and prevent the development of liver cirrhosis and malignancy.

Inflammasomes and Pyroptosis of Liver Cells in Liver Fibrosis

“…Liver fibrosis is characterized by excessive extracellular matrix (ECM) deposition in response to chronic liver injury, including virus infection, non-alcoholic steatohepatitis (NASH), alcoholic liver disease (ALD), and autoimmune diseases ( 3 , 4 ). Generally, activated HSCs are primary myofibroblasts that produce and secrete ECM.…”

Epigenetic Aspects and Prospects in Autoimmune Hepatitis

“…The transcriptional activity of genes occurs within chromatin (86). Chromatin is composed of histones arranged in octamers and double-stranded DNA that makes 1.65 turns around each octamer (38,39,86,87) (Figure 1). Two copies of four core histones (H2A, H2B, H3, and H4) comprise the octamer (38,(86)(87)(88), and each DNA-enwrapped octamer constitutes a nucleosome (89).…”

“…Chromatin is composed of histones arranged in octamers and double-stranded DNA that makes 1.65 turns around each octamer (38,39,86,87) (Figure 1). Two copies of four core histones (H2A, H2B, H3, and H4) comprise the octamer (38,(86)(87)(88), and each DNA-enwrapped octamer constitutes a nucleosome (89). The nucleosomes are linked by a short DNA sequence of 60 base pairs, and the beaded filament is condensed and packaged in the nucleus as chromatin (86).…”

“…Two copies of four core histones (H2A, H2B, H3, and H4) comprise the octamer (38,(86)(87)(88), and each DNA-enwrapped octamer constitutes a nucleosome (89). The nucleosomes are linked by a short DNA sequence of 60 base pairs, and the beaded filament is condensed and packaged in the nucleus as chromatin (86). A histone linker molecule maintains proper packaging of the DNA by binding to the site of DNA entry and exit from each nucleosome (86,87,90).…”

Role of Immune Cells in Biliary Repair

“…The liver possesses vigorous regenerative capability and is the only solid organ in the human body that can fully recover to a normal state under compensated injury ( 6 ). Liver regeneration is a complicated process regulated by multiple mechanisms, including classical signaling pathways as well as epigenetic and posttranscriptional modulation ( 6 – 8 ). As a vital part of the liver, the biliary system also harbors great reparative capacity.…”