Histone methyltransferase G9a protects against acute liver injury through GSTP1

Zhang, Yu; Xue, Weili; Zhang, Wenquan; Yuan, Yangmian; Xiu-qin, Zhu; Wang, Qing; Wei, Yujuan; Yang, Dong; Yang, Chen; Yan, Chen; Sun, Yu; Wang, Shun; Huang, Kun; Zheng, Ling

doi:10.1038/s41418-019-0412-8

Cited by 56 publications

(40 citation statements)

References 37 publications

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“…Primary hepatocytes were isolated from 12-week-old male C57BL/6 mice as we previously reported. 23 For resistin treatment, primary hepatocytes were treated with 300 ng/mL rm-resistin (R&D Systems) for 12 hours, PBS was used as the control. For media treatment, primary hepatocytes were fasted for 2 hours in serum-and glucose-free media; then filtered media from 3T3-L1 cells, which were transfected with phage or phage-Lmo4 (differentiation Day 7 to Day 8), was added, and cultured for 12 hours.…”

Section: Primary Hepatocyte Isolation and Treatmentmentioning

confidence: 99%

Lmo4‐resistin signaling contributes to adipose tissue‐liver crosstalk upon weight cycling

et al. 2020

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Repeated cycles of weight loss and regain, known as weight cycling, is often seen when people try to lose weight. The exact pathophysiological effects and the underlying mechanisms of weight cycling remain largely unclear. Here, we report that weight cycling induced by alternating feeding mice with a low‐fat diet or a high‐fat diet in a 1‐week switch protocol caused further increased epididymal white adipose tissue (eWAT) weight, preadipocyte proliferation, hepatic inflammation, fasting blood glucose level, and glucose intolerance, compared with the continuously HF‐fed mice. Combining the secretory protein database with RNA‐sequencing and quantitative PCR (qPCR) results in eWAT, the mRNA levels of several adipokines, including Retn (encoding resistin), were found altered by weight cycling. A transcriptional co‐factor Lmo4 was found regulated by weight cycling; Lmo4 enhanced preadipocyte proliferation, in vitro adipogenesis, transcription of Retn, and resistin secretion in 3T3‐L1 cells. Primary mouse hepatocytes administrated with recombinant mouse resistin (rm‐resistin), or exposed to media from Lmo4‐overexpressed 3T3‐L1 cells, showed increased inflammatory responses and gluconeogenesis. Furthermore, rm‐resistin‐injected normal chow‐fed mice showed upregulated blood glucose level by increasing gluconeogenesis, and upregulated the hepatic inflammatory responses. Together, our results suggest a regulatory role of Lmo4‐resistin signaling in weight cycling, indicating a crosstalk between the adipose tissue and liver.

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Section: Primary Hepatocyte Isolation and Treatmentmentioning

confidence: 99%

Lmo4‐resistin signaling contributes to adipose tissue‐liver crosstalk upon weight cycling

et al. 2020

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“…A marked increase of H3K9me2 was reported to play a crucial role in epigenetic transcriptional gene silencing and was observed during liver maturation [ 41 ]. Liver-specific G9a-knockout (G9a-liver-KO) mice did not show significant liver injury or inflammation, but these mice had decreased cytochrome P450 enzymes (CYPs) and dysregulated lipid metabolism by hepatocytes [ 42 ]. Moreover, G9a-liver-KO mice displayed more-severe liver injury after lipopolysaccharide or acetaminophen overdose treatment [ 42 , 43 ].…”

Section: Discussionmentioning

confidence: 99%

“…Liver-specific G9a-knockout (G9a-liver-KO) mice did not show significant liver injury or inflammation, but these mice had decreased cytochrome P450 enzymes (CYPs) and dysregulated lipid metabolism by hepatocytes [ 42 ]. Moreover, G9a-liver-KO mice displayed more-severe liver injury after lipopolysaccharide or acetaminophen overdose treatment [ 42 , 43 ]. Interestingly, other studies revealed that animals with muscle-specific G9a-knockout were resistant to high-fat diet-induced obesity and hepatic steatosis [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Histone Methyltransferase G9a-Promoted Progression of Hepatocellular Carcinoma Is Targeted by Liver-Specific Hsa-miR-122

Yuan

Lee

Yang

et al. 2021

Cancers

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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.

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“… 1 , 5 , 28 Recently, histone methylation has been considered to be involved in the regulation of liver injury. 29 , 30 For example, EZH2, which catalyzes H3K27me3, contributed to the pathogenesis of liver failure through triggering TNF and other indispensable proinflammatory cytokines. 30 We found that inhibition of Dot1L, a H3K79 methyltransferase, ameliorated liver injury, and improved survival rate of FH in mice through inhibiting activation, proliferation, and cytokine production of CD4 + T cells in vivo.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Dot1L Alleviates Fulminant Hepatitis Through Myeloid-Derived Suppressor Cells

Yang

Huang

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims Fulminant hepatitis (FH) is a clinical syndrome characterized by sudden and severe liver dysfunction. Dot1L, a histone methyltransferase, is implicated in various physiologic and pathologic processes, including transcription regulation and leukemia. However, the role of Dot1L in regulating inflammatory responses during FH remains elusive. Methods Propionibacterium acnes ( P. acnes )-primed, lipopolysaccharides (LPS)-induced FH was established in C57BL/6 mice and was treated with the Dot1L inhibitor EPZ-5676. Myeloid derived suppressor cells (MDSCs) were depleted by anti-Gr-1 antibody to evaluate their therapeutic roles in Dot1L treatment of FH. Moreover, peripheral blood of patients suffered with FH and healthy controls was collected to determine the expression profile of Dot1L-SOCS1-iNOS axis in their MDSCs. Results Here we identified that EPZ-5676, pharmacological inhibitor of Dot1L, attenuated the liver injury of mice subjected to FH. Dot1L inhibition led to decreased T helper 1 cell response and expansion of regulatory T cells (Tregs) during FH. Interestingly, Dot1L inhibition didn’t directly target T cells, but dramatically enhanced the immunosuppressive function of MDSCs. Mechanistically, Dot1L inhibition epigenetically suppressed SOCS1 expression, thus inducing inducible nitric oxide synthase (iNOS) expression in a STAT1-dependent manner. Moreover, in human samples, the levels of Dot1L and SOCS1 expression were upregulated in MDSCs, accompanied by decreased expression of iNOS in patients with FH, compared with healthy controls. Conclusions Altogether, our findings established Dot1L as a critical regulator of MDSC immunosuppressive function for the first time, and highlighted the therapeutic potential of Dot1L inhibitor for FH treatment.

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Histone methyltransferase G9a protects against acute liver injury through GSTP1

Cited by 56 publications

References 37 publications

Lmo4‐resistin signaling contributes to adipose tissue‐liver crosstalk upon weight cycling

Lmo4‐resistin signaling contributes to adipose tissue‐liver crosstalk upon weight cycling

Histone Methyltransferase G9a-Promoted Progression of Hepatocellular Carcinoma Is Targeted by Liver-Specific Hsa-miR-122

Inhibition of Dot1L Alleviates Fulminant Hepatitis Through Myeloid-Derived Suppressor Cells

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