Dataset Information

Identification of an epigenetic signature of early mouse liver regeneration that is disrupted by Zn-HDAC inhibition.

ABSTRACT: Liver regeneration has been well studied with hope of discovering strategies to improve liver disease outcomes. Nevertheless, the signals that initiate such regeneration remain incompletely defined, and translation of mechanism-based pro-regenerative interventions into new treatments for hepatic diseases has not yet been achieved. We previously reported the isoform-specific regulation and essential function of zinc-dependent histone deacetylases (Zn-HDACs) during mouse liver regeneration. Those data suggest that epigenetically regulated anti-proliferative genes are deacetylated and transcriptionally suppressed by Zn-HDAC activity or that pro-regenerative factors are acetylated and induced by such activity in response to partial hepatectomy (PH). To investigate these possibilities, we conducted genome-wide interrogation of the liver histone acetylome during early PH-induced liver regeneration in mice using acetyL-histone chromatin immunoprecipitation and next generation DNA sequencing. We also compared the findings of that study to those seen during the impaired regenerative response that occurs with Zn-HDAC inhibition. The results reveal an epigenetic signature of early liver regeneration that includes both hyperacetylation of pro-regenerative factors and deacetylation of anti-proliferative and pro-apoptotic genes. Our data also show that administration of an anti-regenerative regimen of the Zn-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) not only disrupts gene-specific pro-regenerative changes in liver histone deacetylation but also reverses PH-induced effects on histone hyperacetylation. Taken together, these studies offer new insight into and suggest novel hypotheses about the epigenetic mechanisms that regulate liver regeneration.

SUBMITTER: Huang J

PROVIDER: S-EPMC4623439 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of an epigenetic signature of early mouse liver regeneration that is disrupted by Zn-HDAC inhibition.

Huang Jiansheng J Schriefer Andrew E AE Yang Wei W Cliften Paul F PF Rudnick David A DA

Epigenetics 20141101 11

Liver regeneration has been well studied with hope of discovering strategies to improve liver disease outcomes. Nevertheless, the signals that initiate such regeneration remain incompletely defined, and translation of mechanism-based pro-regenerative interventions into new treatments for hepatic diseases has not yet been achieved. We previously reported the isoform-specific regulation and essential function of zinc-dependent histone deacetylases (Zn-HDACs) during mouse liver regeneration. Those ...[more]

PMID: 25482284

Similar Datasets

Project description:The inhibitory effect of dextrose supplementation on liver regeneration was first described more than 4 decades ago. Nevertheless, the molecular mechanisms responsible for this observation have not been elucidated. We investigated these mechanisms using the partial hepatectomy model in mice given standard or 10% dextrose (D10)-supplemented drinking water. The results showed that D10-treated mice exhibited significantly reduced hepatic regeneration compared with controls, as assessed by hepatocellular bromodeoxyuridine (BrdU) incorporation and mitotic frequency. D10 supplementation did not suppress activation of hepatocyte growth factor (HGF), induction of transforming growth factor alpha (TGF-alpha) expression, or tumor necrosis factor alpha-interleukin-6 cytokine signaling, p42/44 extracellular signal-regulated kinase (ERK) activation, immediate early gene expression, or expression of CCAAT/enhancer binding protein beta (C/EBPbeta), but did augment expression of the mito-inhibitory factors C/EBPalpha, p21(Waf1/Cip1), and p27(Kip1). In addition, forkhead box M1 (FoxM1) expression, which is required for normal liver regeneration, was suppressed by D10 treatment. Finally, D10 did not suppress either FoxM1 expression or hepatocellular proliferation in p21 null mice subjected to partial hepatectomy, establishing the functional significance of these events in mediating the effects of D10 on liver regeneration.These data show that the inhibitory effect of dextrose supplementation on liver regeneration is associated with increased expression of C/EBPalpha, p21, and p27, and decreased expression of FoxM1, and that D10-mediated inhibition of liver regeneration is abrogated in p21-deficient animals. Our observations are consistent with a model in which hepatic sufficiency is defined by homeostasis between the energy-generating capacity of the liver and the energy demands of the body mass, with liver regeneration initiated when the functional liver mass is no longer sufficient to meet such demand.

Dataset Information

Identification of an epigenetic signature of early mouse liver regeneration that is disrupted by Zn-HDAC inhibition.

Publications

Identification of an epigenetic signature of early mouse liver regeneration that is disrupted by Zn-HDAC inhibition.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets