The role of H19, a long non-coding RNA, in mouse liver postnatal maturation

Pope, Chad; Piekos, Stephanie; Mishra, S. K.; Zhong, Xiao‐bo

doi:10.1371/journal.pone.0187557

Cited by 14 publications

(12 citation statements)

References 40 publications

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“…48 It was reported that deletion of a nuclease-sensitive region between the Igf2 and H19 genes led to Igf2 misregulation and increased adiposity. 50 One important aspect of biological functions for H19 is to regulate lineage-specific differentiation of MSCs. Subconfluent mouse hepatocyte iHPx cells were infected with Ad-H19, Ad-siH19, Ad-siMlxipl, Ad-H19 + Ad-siMlxip or Ad-RFP for 36 h. The infected hepatocytes were collected and subcutaneously injected into the flanks of athymic nude mice for 10 d. Masses at the injection sites were retrieved, fixed and snap-frozen or paraffin embedded.…”

Section: Discussionmentioning

confidence: 99%

“…H19 may regulate hepatic lipid metabolism through at least two pathways, the mTOR signalling axis and Mlxipl-regulated transcription network in hepatocytes possibly resulted from activating Wnt/β-catenin and/or IGF2 signalling pathways. 50 One important aspect of biological functions for H19 is to regulate lineage-specific differentiation of MSCs. We found that H19 plays an important role in regulating BMP9-regulated lineage-specific differentiation of MSCs.…”

Section: Discussionmentioning

confidence: 99%

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Long non‐coding RNA (lncRNA) H19 induces hepatic steatosis through activating MLXIPL and mTORC1 networks in hepatocytes

Wang

Cao

Shu

et al. 2019

J Cellular Molecular Medi

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Liver plays an essential role in regulating lipid metabolism, and chronically disturbed hepatic metabolism may cause obesity and metabolic syndrome, which may lead to non-alcoholic fatty liver disease (NAFLD). Increasing evidence indicates long noncoding RNAs (lncRNAs) play an important role in energy metabolism. Here, we investigated the role of lncRNA H19 in hepatic lipid metabolism and its potential association with NAFLD. We found that H19 was up-regulated in oleic acid-induced steatosis and during the development of high-fat diet (HFD)-induced NAFLD. Exogenous overexpression of H19 in hepatocytes induced lipid accumulation and up-regulated the expression of numerous genes involved in lipid synthesis, storage and breakdown, while silencing endogenous H19 led to a decreased lipid accumulation in hepatocytes. Mechanistically, H19 was shown to promote hepatic steatosis by up-regulating lipogenic transcription factor MLXIPL. Silencing Mlxipl diminished H19-induced lipid accumulation in hepatocytes. Furthermore, H19-induced lipid accumulation was effectively inhibited by PI3K/mTOR inhibitor PF-04691502. Accordingly, H19 overexpression in hepatocytes up-regulated most components of the mTORC1 signalling axis, which were inhibited by silencing endogenous H19. In vivo hepatocyte implantation studies further confirm that H19 promoted hepatic steatosis by up-regulating both mTORC1 signalling axis and MLXIPL transcriptional network. Collectively, these

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long non‐coding RNA (lncRNA) H19 induces hepatic steatosis through activating MLXIPL and mTORC1 networks in hepatocytes

Wang

Cao

Shu

et al. 2019

J Cellular Molecular Medi

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“…Igf2 and H19 are adjacent, imprinted genes [74] that show aberrant imprinting and epigenetic abnormalities in HCC [29]. H19 is highly expressed in proliferative tissues, including liver regeneration after injury [74], and its first exon encodes miR-675, whose overexpression promotes liver cancer [62]. The strong up regulation of these three genes in female E1/E2-KO livers suggests E1/E2-KO female mice may show increased susceptibility to HCC compared to wild-type female liver in response to CCl 4 and other hepatotoxins.…”

Section: Discussionmentioning

confidence: 99%

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Lau-Corona

Bae

Hennighausen

et al. 2019

Preprint

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31Background: Sex differences in the incidence and progression of many liver diseases, including liver 32 fibrosis and hepatocellular carcinoma, are associated with sex-biased expression of hundreds of 33 genes in the liver. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary 34 growth hormone secretion, which controls a transcriptional regulatory network operative in the context 35 of sex-biased chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive 36 chromatin mark that is specifically deposited by polycomb repressive complex-2, via its homologous 37 catalytic subunits Ezh1 and Ezh2, at many strongly female-biased genes in male mouse liver, but not 38 at male-biased genes in female liver. Results: We used Ezh1-knockout mice with a hepatocyte-39 specific knockout of Ezh2 to elucidate the sex bias of liver H3K27-trimethylation and its functional role 40 in regulating sex-differences in the liver. Combined hepatic Ezh1/Ezh2 deficiency led to a significant 41 loss of sex-biased gene expression, particularly in male liver, where many female-biased genes 42 increased in expression while male-biased genes showed decreased expression. The associated loss 43 of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also 44 more pronounced in male liver. Many genes linked to liver fibrosis and hepatocellular carcinoma were 45 induced in Ezh1/Ezh2-deficient livers, which may contribute to the increased sensitivity of these mice 46 to hepatotoxin-induced liver pathology. Conclusions: Ezh1/Ezh2-catalyzed H3K27-trimethyation is 47 thus essential for the sex-dependent epigenetic regulation of liver chromatin states controlling 48 phenotypic sex differences in liver metabolism and liver fibrosis, and may be a critical determinant of 49 the sex-bias in liver disease susceptibility. Background 52Liver disease shows marked sex differences. Hepatocellular carcinoma incidence and mortality is 53 three times higher in men than in women [1, 2], and male mice are more susceptible to chemical-54 induced hepatic carcinogenesis [3]. Males are also more susceptible to non-alcoholic fatty liver 55 disease, non-alcoholic steatohepatitis and liver fibrosis than females [4][5][6][7][8]. Underlying these sex-biased Lau-Corona et alPage 5 3/13/19 liver. Hepatic Ezh1/Ezh2 deficiency is also shown to down regulate many male-biased genes, 106presumed as a secondary response to the disruption of female-biased gene expression. Finally, we 107show that many genes associated with liver fibrosis and liver carcinogenesis are differentially 108 responsive to the loss of Ezh1/Ezh2 in male compared to female liver, which may contribute to the 109 observed sex-differences in the incidence and progression of liver cancer. 110 111 Methods 112 Animal tissues. Livers from 7-week-old male and female Ezh1-knockout mice with a hepatocyte-113 specific knockout of Ezh2 (E1/E2-KO mice, also designated Double-knockout (DKO) in the figures 114 and tables) and their age and sex...

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“…These genes include Igf2, H19 and miR675 (Fig 7E, S11 Table ). Igf2 and H19 are adjacent, imprinted genes [67] that show aberrant imprinting and epigenetic abnormalities in HCC [29]. H19 is highly expressed in proliferative tissues, including liver regenerating after injury [67], and its first exon encodes miR-675, whose overexpression promotes liver cancer [50].…”

Section: Plos Geneticsmentioning

confidence: 99%

“…Igf2 and H19 are adjacent, imprinted genes [67] that show aberrant imprinting and epigenetic abnormalities in HCC [29]. H19 is highly expressed in proliferative tissues, including liver regenerating after injury [67], and its first exon encodes miR-675, whose overexpression promotes liver cancer [50]. The strong up regulation of these three genes in E1/E2-KO female liver suggests female E1/E2-KO mice may show increased susceptibility to liver toxicity and HCC compared to female wild-type mice, e.g., in response to hepatotoxins such as carbon tetrachloride.…”

Section: Plos Geneticsmentioning

confidence: 99%

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

et al. 2020

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Sex differences in the incidence and progression of many liver diseases, including liver fibrosis and hepatocellular carcinoma, are associated with sex-biased hepatic expression of hundreds of genes. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary growth hormone secretion, which controls a transcriptional regulatory network operative in the context of sex-biased and growth hormone-regulated chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive chromatin mark deposited at many strongly female-biased genes in male mouse liver, but not at male-biased genes in female liver, and is catalyzed by polycomb repressive complex-2 through its homologous catalytic subunits, Ezh1 and Ezh2. Here, we used Ezh1-knockout mice with a hepatocytespecific knockout of Ezh2 to investigate the sex bias of liver H3K27-trimethylation and its functional role in regulating sex-differences in the liver. Combined hepatic Ezh1/Ezh2 deficiency led to a significant loss of sex-biased gene expression, particularly in male liver, where many female-biased genes were increased in expression while male-biased genes showed decreased expression. The associated loss of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also more pronounced in male liver. Further, Ezh1/Ezh2 deficiency in male liver, and to a lesser extent in female liver, led to up regulation of many genes linked to liver fibrosis and liver cancer, which may contribute to the observed liver pathologies and the increased sensitivity of these mice to hepatotoxin exposure. Thus, Ezh1/Ezh2-catalyzed H3K27-trimethyation regulates sex-dependent genetic programs in liver metabolism and liver fibrosis through its sex-dependent effects on the epigenome, and may thereby determine the sex-bias in liver disease susceptibility.

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The role of H19, a long non-coding RNA, in mouse liver postnatal maturation

Cited by 14 publications

References 40 publications

Long non‐coding RNA (lncRNA) H19 induces hepatic steatosis through activating MLXIPL and mTORC1 networks in hepatocytes

Long non‐coding RNA (lncRNA) H19 induces hepatic steatosis through activating MLXIPL and mTORC1 networks in hepatocytes

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

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