title: Cytosine modifications modulate the chromatin architecture of transcriptional enhancers.
abstract: Epigenetic mechanisms are believed to play key roles in the establishment of cell-specific transcription programs. Accordingly, the modified bases 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) have been observed in DNA of genomic regulatory regions such as enhancers, and oxidation of 5mC into 5hmC by Ten-eleven translocation (TET) proteins correlates with enhancer activation. However, the functional relationship between cytosine modifications and the chromatin architecture of enhancers remains elusive. To gain insights into their function, 5mC and 5hmC levels were perturbed by inhibiting DNA methyltransferases and TETs during differentiation of mouse embryonal carcinoma cells into neural progenitors, and chromatin characteristics of enhancers bound by the pioneer transcription factors FOXA1, MEIS1, and PBX1 were interrogated. In a large fraction of the tested enhancers, inhibition of DNA methylation was associated with a significant increase in monomethylation of H3K4, a characteristic mark of enhancer priming. In addition, at some specific enhancers, 5mC oxidation by TETs facilitated chromatin opening, a process that may stabilize MEIS1 binding to these genomic regions.
authors.affiliation: CNRS UMR6290, Equipe SP@RTE, Institut de Génétique et Développement de Rennes, Campus de Beaulieu, 35042 Rennes Cedex, France.|Université de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France.
authors.forename: Elise A
authors.initials: EA
authors.lastname: Mahé
authors.affiliation: CNRS UMR6290, Equipe SP@RTE, Institut de Génétique et Développement de Rennes, Campus de Beaulieu, 35042 Rennes Cedex, France.|Université de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Madigou
authors.affiliation: EMBL, Heidelberg 69117, Germany.
authors.forename: Aurélien A
authors.initials: AA
authors.lastname: Sérandour
authors.affiliation: CNRS UMR6290, Equipe SP@RTE, Institut de Génétique et Développement de Rennes, Campus de Beaulieu, 35042 Rennes Cedex, France.|Université de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Bizot
authors.affiliation: CNRS UMR6290, Equipe SP@RTE, Institut de Génétique et Développement de Rennes, Campus de Beaulieu, 35042 Rennes Cedex, France.|Université de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Avner
authors.affiliation: Inserm U1085-IRSET, Université de Rennes 1, F-35042 Rennes, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Chalmel
authors.affiliation: CNRS UMR6290, Equipe SP@RTE, Institut de Génétique et Développement de Rennes, Campus de Beaulieu, 35042 Rennes Cedex, France.|Université de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Palierne
authors.affiliation: CNRS UMR6290, Equipe SP@RTE, Institut de Génétique et Développement de Rennes, Campus de Beaulieu, 35042 Rennes Cedex, France.|Université de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France.
authors.forename: Raphaël
authors.initials: R
authors.lastname: Métivier
authors.affiliation: CNRS UMR6290, Equipe SP@RTE, Institut de Génétique et Développement de Rennes, Campus de Beaulieu, 35042 Rennes Cedex, France.|Université de Rennes 1, Campus de Beaulieu, 35042 Rennes Cedex, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Salbert
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D002843:Chromatin / Q000378:metabolism* / Q000648:ultrastructure; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases; D054278:Embryonal Carcinoma Stem Cells / Q000166:cytology / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D044127:Epigenesis, Genetic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D000075062:Pre-B-Cell Leukemia Transcription Factor 1 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D002843:Chromatin; D004268:DNA-Binding Proteins; C496500:Foxa1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; D006657:Histones; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D000076123:DNA (Cytosine-5-)-Methyltransferase 1