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Dynamic hydroxymethylation of deoxyribonucleic acid marks differentiation-associated enhancers.

Abstract : Enhancers are developmentally controlled transcriptional regulatory regions whose activities are modulated through histone modifications or histone variant deposition. In this study, we show by genome-wide mapping that the newly discovered deoxyribonucleic acid (DNA) modification 5-hydroxymethylcytosine (5hmC) is dynamically associated with transcription factor binding to distal regulatory sites during neural differentiation of mouse P19 cells and during adipocyte differentiation of mouse 3T3-L1 cells. Functional annotation reveals that regions gaining 5hmC are associated with genes expressed either in neural tissues when P19 cells undergo neural differentiation or in adipose tissue when 3T3-L1 cells undergo adipocyte differentiation. Furthermore, distal regions gaining 5hmC together with H3K4me2 and H3K27ac in P19 cells behave as differentiation-dependent transcriptional enhancers. Identified regions are enriched in motifs for transcription factors regulating specific cell fates such as Meis1 in P19 cells and PPARγ in 3T3-L1 cells. Accordingly, a fraction of hydroxymethylated Meis1 sites were associated with a dynamic engagement of the 5-methylcytosine hydroxylase Tet1. In addition, kinetic studies of cytosine hydroxymethylation of selected enhancers indicated that DNA hydroxymethylation is an early event of enhancer activation. Hence, acquisition of 5hmC in cell-specific distal regulatory regions may represent a major event of enhancer progression toward an active state and participate in selective activation of tissue-specific genes.
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https://www.hal.inserm.fr/inserm-00716879
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Submitted on : Wednesday, July 11, 2012 - 5:51:24 PM
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Long-term archiving on: : Friday, October 12, 2012 - 2:55:22 AM

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Aurélien A. Sérandour, Stéphane Avner, Frédérik Oger, Maud Bizot, Frédéric Percevault, et al.. Dynamic hydroxymethylation of deoxyribonucleic acid marks differentiation-associated enhancers.. Nucleic Acids Research, Oxford University Press, 2012, 40 (17), pp.8255-65. ⟨10.1093/nar/gks595⟩. ⟨inserm-00716879⟩

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