title: 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.
authors.affiliation: a Department of Pediatrics ; Washington University School of Medicine ; St. Louis , MO USA.
authors.forename: Jiansheng
authors.initials: J
authors.lastname: Huang
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Schriefer
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Paul F
authors.initials: PF
authors.lastname: Cliften
authors.forename: David A
authors.initials: DA
authors.lastname: Rudnick
mesh_terms: D000107:Acetylation; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006498:Hepatectomy; D059014:High-Throughput Nucleotide Sequencing; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000502:physiology / Q000601:surgery; D008115:Liver Regeneration / Q000235:genetics*; D051379:Mice; D000077337:Vorinostat; D015032:Zinc / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D000077337:Vorinostat; D006655:Histone Deacetylases; D015032:Zinc
keywords: Ac-H3K9, histone H3 acetylated on lysine 9; CDKI, cyclin dependent kinase inhibitor; ChIP-Seq, chromatin immunoprecipitation-next generation DNA sequencing; GO, gene ontology; PH, partial hepatectomy; SAHA, suberoylanilide hydroxamic acid; TSS, transcription start sites; Zn-HDAC, zinc-dependent histone deacetylase; chromatin immunoprecipitation; histone acetylation; histone deacetylase; partial hepatectomy; qRT-PCR, semi-quantitative real-time reverse-transcription polymerase-chain-reaction; suberoylanilide hydroxamic acid