Journal
NUCLEIC ACIDS RESEARCH
Volume 40, Issue 17, Pages 8255-8265Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gks595
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Funding
- Ligue National Contre le Cancer [Equipe Labellisee Ligue]
- Agence Nationale pour la Recherche [ANR-09-BLAN-0268-01]
- Region Bretagne [CREATE-DYNAMED-4793, SAD 08HC-315-02]
- OSEO-ANVAR [IT-DIAB]
- Ministere de la Recherche
- CNRS
- MRC [G1002084] Funding Source: UKRI
- Agence Nationale de la Recherche (ANR) [ANR-09-BLAN-0268] Funding Source: Agence Nationale de la Recherche (ANR)
- Medical Research Council [G1002084] Funding Source: researchfish
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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 PPAR gamma 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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