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Abstract
A basic question linked to differential patterns of gene expression is how cells reach different fates despite using the same DNA template. Since 5-hydroxymethylcytosine (5hmC) emerged as an intermediate metabolite in active DNA demethylation, there have been increasing efforts to elucidate its function as a stable modification of the genome, including a role in establishing such tissue-specific patterns of expression. Recently we described TET1-mediated enrichment of 5hmC on the promoter region of the master regulator of hepatocyte identity, HNF4A, which precedes differentiation of liver adult progenitor cells in vitro. Here, we studied the genome-wide distribution of 5hmC at early in vitro differentiation of human hepatocyte-like cells. We found a global increase in 5hmC as well as a drop in 5-methylcytosine after one week of in vitro differentiation from bipotent progenitors, at a time when the liver transcript program is already established. 5hmC was overall higher at the bodies of overexpressed genes. Furthermore, by modifying the metabolic environment, an adenosine derivative prevents 5hmC enrichment and impairs the acquisition of hepatic identity markers. These results suggest that 5hmC could be a marker of cell identity, as well as a useful biomarker in conditions associated with cell de-differentiation such as liver malignancies.
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1 Department of Cellular Biology and Development, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior s/n, Ciudad Universitaria, Coyoacán, Mexico (GRID:grid.9486.3) (ISNI:0000 0001 2159 0001)
2 Institute of Biology Valrose (iBV), The National Center for Scientific Research (CNRS) - National Institute of Health and Medical Research (Inserm), Université Côte d’Azur, Nice, France (GRID:grid.9486.3)
3 Department of Immunity, Virus and Inflammation. Cancer Research Centre of Lyon (CRCL), Inserm U 1052, CNRS UMR 5286, Université de Lyon, Centre Léon Bérard, 28 rue Laennec, 69373, Lyon, France (GRID:grid.9486.3)
4 Molecular Mechanisms and Biomarkers Group, International Agency for Research on Cancer (IARC), Lyon, France (GRID:grid.17703.32) (ISNI:0000000405980095)
5 Department of Cellular Biology and Development, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior s/n, Ciudad Universitaria, Coyoacán, Mexico (GRID:grid.9486.3) (ISNI:0000 0001 2159 0001); Division of Biomedical Research, Centro Médico Nacional “20 de noviembre”, ISSSTE, San Lorenzo 502, Benito Juárez, Mexico (GRID:grid.420239.e) (ISNI:0000 0001 2113 9210)
6 INSERM U1052, CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon Université Claude Bernard, Lyon, France (GRID:grid.7849.2) (ISNI:0000 0001 2150 7757)
7 Department of Molecular Genetics, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Circuito Exterior s/n, Ciudad Universitaria, Coyoacán, Mexico (GRID:grid.9486.3) (ISNI:0000 0001 2159 0001)
8 Department of Immunity, Virus and Inflammation. Cancer Research Centre of Lyon (CRCL), Inserm U 1052, CNRS UMR 5286, Université de Lyon, Centre Léon Bérard, 28 rue Laennec, 69373, Lyon, France (GRID:grid.9486.3); Department of Translational Research and Innovation. Centre Léon Bérard, 28 rue Laennec, 69373, Lyon, France (GRID:grid.9486.3)