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Liver-specific knockout of histone methyltransferase G9a impairs liver maturation and dysregulates inflammatory, cytoprotective, and drug-processing genes.

ABSTRACT: Methyltransferase G9a is essential for a key gene silencing mark, histone H3 dimethylation at lysine-9 (H3K9me2). Hepatic G9a expression is down-regulated by xenobiotics and diabetes. However, little is known about the role of G9a in liver. Thus, we generated mice with liver-specific knockout (Liv-KO) of G9a. Adult G9a Liv-KO mice had marked loss of H3K9me2 proteins in liver, without overt liver injury or infiltration of inflammatory cells. However, G9a-null livers had ectopic induction of certain genes normally expressed in neural and immune systems. Additionally, G9a-null livers had moderate down-regulation of cytoprotective genes, markedly altered expression of certain important drug-processing genes, elevated endogenous reactive oxygen species, induction of ER stress marker Chop, but decreased glutathione and nuclear Nrf2. microRNA-383, a negative regulator of the PI3K/Akt pathway, was strongly induced in G9a Liv-KO mice. After LPS treatment, G9a Liv-KO mice had aggravated lipid peroxidation and proinflammatory response. Taken together, the present study demonstrates that G9a regulates liver maturation by silencing neural and proinflammatory genes but maintaining/activating cytoprotective and drug-processing genes, in which the G9a/miR-383/PI3K/Akt/Nrf2?(Chop) pathways may play important roles. G9a deficiency due to genetic polymorphism and/or environmental exposure may alter xenobiotic metabolism and aggravate inflammation and liver dysfunction.

SUBMITTER: Lu H

PROVIDER: S-EPMC7745776 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Liver-specific knockout of histone methyltransferase G9a impairs liver maturation and dysregulates inflammatory, cytoprotective, and drug-processing genes.

Lu Hong H Lei Xiaohong X Zhang Qinghao Q

Xenobiotica; the fate of foreign compounds in biological systems 20180723 6

Methyltransferase G9a is essential for a key gene silencing mark, histone H3 dimethylation at lysine-9 (H3K9me2). Hepatic G9a expression is down-regulated by xenobiotics and diabetes. However, little is known about the role of G9a in liver. Thus, we generated mice with liver-specific knockout (Liv-KO) of G9a. Adult G9a Liv-KO mice had marked loss of H3K9me2 proteins in liver, without overt liver injury or infiltration of inflammatory cells. However, G9a-null livers had ectopic induction of certa ...[more]

PMID: 29912608

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Project description:Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers, which is the second most lethal tumor worldwide. Epigenetic deregulation is a common trait observed in HCC. Recently, increasing evidence suggested that the G9a histone methyltransferase might be a novel regulator of HCC development. However, several HCC cell lines were recently noted to have HeLa cell contamination or to have been derived from non-hepatocellular origin, suggesting that functional validation of G9a in proper HCC models is still required. Herein, we first confirmed that higher G9a messenger RNA and protein expression levels were correlated with poor overall survival (OS) and disease-free survival (DFS) rates of HCC patients from The Cancer Genome Atlas (TCGA) dataset and our recruited HCC cohort. In an in vitro functional evaluation of HCC cells, HCC36 (hepatitis B virus-positive (HBV+) and Mahlavu (HBV-)) cells showed that G9a participated in promoting cell proliferation, colony formation, and migration/invasion abilities. Moreover, orthotopic inoculation of G9a-depleted Mahlavu cells in NOD-SCID mice also resulted in a significantly decreased tumor burden compared to the control group. Furthermore, after surveying microRNA (miRNA; miR) prediction databases, we identified the liver-specific miR-122 as a G9a-targeting miRNA. In various HCC cell lines, we observed that miR-122 expression levels tended to be inversely correlated to G9a expression levels. In clinical HCC specimens, a significant inverse correlation of miR-122 and G9a mRNA expression levels was also observed. Functionally, the colony formation and invasive ability were attenuated in miR-122-overexpressing HCC cells. HCC patients with low miR-122 and high G9a expression levels had the worst OS and DFS rates compared to others. Together, our results confirmed the importance of altered G9a expression during HCC progression and discovered that a novel liver-specific miR-122-G9a regulatory axis exists.

Dataset Information

Liver-specific knockout of histone methyltransferase G9a impairs liver maturation and dysregulates inflammatory, cytoprotective, and drug-processing genes.

Publications

Liver-specific knockout of histone methyltransferase G9a impairs liver maturation and dysregulates inflammatory, cytoprotective, and drug-processing genes.

Similar Datasets

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