Mechanism and Therapeutic Opportunities of Histone Modifications in Chronic Liver Disease - PubMed (original) (raw)

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Mechanism and Therapeutic Opportunities of Histone Modifications in Chronic Liver Disease

Qiuyu Cai et al. Front Pharmacol. 2021.

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.

Keywords: alcoholic liver disease; histone acetylation; histone methylation; histone phosphorylation; liver cirrhosis; liver fibrosis; metabolic associated fatty liver disease; viral hepatitis.

Copyright © 2021 Cai, Gan, Tang, Wu and Gao.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1

FIGURE 1

Structure and modifications of histones. (A) Four core histone proteins (H2A, H2B, H3, and H4) and one linker histone H1 which binds to the site where DNA enters and exits the nucleosome core particle, form a complete nucleosome. Post-translational modifications (PTMs) occur on histone terminal tails, which are accessible on the surface of the nucleosome. (B) The nucleosomes are linked by a sequence of DNA (∼60 bp) and are assembled into beaded chromatin filaments. (C) The potential acetylation, methylation, phosphorylation, and ubiquitination sites of the four core histones are shown. (D) A large array of proteins are involved in regulating and interpreting these PTMs, including readers, writers, and erasers.

FIGURE 2

FIGURE 2

Signaling regulations of histone modification in CLDs. In CLD, hepatocytes, HSCs, LSECs and cholangiocytes undergo histone modifications via the regulation of the writers and erasers, and these modifications are recognized by readers. ALD: alcoholic liver disease; MAFLD: metabolic-associated fatty liver disease; DILI: Drug-induced liver injury; HSC: hepatic stellate cell; LSEC: liver sinusoidal endothelial cell.

FIGURE 3

FIGURE 3

Underlying mechanisms of histone modifications in CLDs. The main histone modifications, the targeted genes, the corresponding effects and the therapeutic targets in CLDs were shown. (A) Modifications of histones are mediated via writers and erasers, and are recognized by readers. These modifications work through changing the expression of corresponding genes. (B) In ALD, p300, HDAC, and BRD4 mediate the histone modifications at specific genes, which regulate lipid and alcohol metabolisms and inflammation reaction. (C) In MAFLD, p300/CBP, HDAC1, SET7/9 et al. mediate the histone modifications at specific genes, which promote chronic inflammation, lipid and glucose metabolism and oxidative stress. (D) In viral hepatitis, PRMT5, HDAC1, BRD4 et al. mediate the histone modifications at specific genes, which regulate HBV replication, cccDNA accumulation and transcription. (E) In autoimmune liver disease, p300 and other proteins mediate the histone modifications at specific genes, which promote T cell proliferation, INF production and cholangiocyte senescence. (F) In liver fibrosis/cirrhosis, p300, SET7/9, HDAC 3 et al. mediate the histone modifications at specific genes, which promote HSC activation, ECM accumulation and chronic inflammation. ALD: alcoholic liver disease; MAFLD: metabolic-associated fatty liver disease; HSC: hepatic stellate cell; IFN: interferon; ECM: extracellular matrix.

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