6533b873fe1ef96bd12d583d
RESEARCH PRODUCT
Histone Variant MacroH2A1 Marks Liver Aging and Orchestrates the Escape from Senescence Induced by DNA Hypomethylation in Hepatocellular Carcinoma
C. PanebiancoCaterina FusilliIllar PataManlio VinciguerraMichela BorghesanMarcus BuschbeckValerio PazienzaJohn M. SedivyFrancesca RappaCappello FTommaso Mazzasubject
SenescencebiologyCell growthCell cycleBiochemistryCell biologyHistoneGeneticsbiology.proteinGene silencingEpigeneticsMolecular BiologyGeneBiotechnologyDNA hypomethylationdescription
The epigenetic basis of age-associated progression of liver diseases towards hepatocellular carcinoma (HCC) is unclear. MacroH2A1 is a variant of histone H2A1, present in the two isoforms, with fundamental roles in cell homeostasis. MacroH2A1 is a marker of senescence associated heterochromatic foci (SAHF) and synergizes with DNA demethylating chemotherapic agent 5-aza-2'-deoxycytidine (5-aza-dC) in silencing tumor suppressor genes in human fibroblasts. We show that protein levels of macroH2A1 isoforms are increased in the livers of old rodents and humans, and in human HCC tissue. Human HCC cells overexpressing macroH2A1 escape a 5-aza-dC-induced senescent phenotype, as determined by cell proliferation/migration/cell cycle assays and b-gal staining, and exhibit a synergistic global DNA hypomethylation. Deletion of macroH2A1 had opposite, pro-senescence effects in presence of drug dependent DNA hypomethylation. System analysis of ChIP-Seq combined with RNA-Seq data revealed complex macroH2A1 genome occupan...
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2015-04-01 |