Abstract
Covalent modification of DNA distinguishes cellular identities and is crucial for regulating the pluripotency and differentiation of embryonic stem (ES) cells. The recent demonstration that 5-methylcytosine (5-mC) may be further modified to 5-hydroxymethylcytosine (5-hmC) in ES cells has revealed a novel regulatory paradigm to modulate the epigenetic landscape of pluripotency. To understand the role of 5-hmC in the epigenomic landscape of pluripotent cells, here we profile the genome-wide 5-hmC distribution and correlate it with the genomic profiles of 11 diverse histone modifications and six transcription factors in human ES cells. By integrating genomic 5-hmC signals with maps of histone enrichment, we link particular pluripotency-associated chromatin contexts with 5-hmC. Intriguingly, through additional correlations with defined chromatin signatures at promoter and enhancer subtypes, we show distinct enrichment of 5-hmC at enhancers marked with H3K4me1 and H3K27ac. These results suggest potential role(s) for 5-hmC in the regulation of specific promoters and enhancers. In addition, our results provide a detailed epigenomic map of 5-hmC from which to pursue future functional studies on the diverse regulatory roles associated with 5-hmC.
Highlights
The potency and fate of a cell can be influenced strongly by the covalent modification of cytosine methylation at carbon five
We show that 5-hmC is an important epigenetic modification associated with the pluripotent state that could play role(s) in a subset of promoters and enhancers with defined chromatin signatures in embryonic stem (ES) cells
To unravel the biology of 5-hmC, we recently developed a selective chemical labeling method for 5-hmC by using T4 bacteriophage ß-glucosyltransferase to transfer an engineered glucose moiety containing an azide group onto the hydroxyl group of 5-hmC, which in turn can chemically incorporate a biotin group for detection, affinity enrichment, and sequencing
Summary
The potency and fate of a cell can be influenced strongly by the covalent modification of cytosine methylation at carbon five. DNAmethylation-mediated epigenomic processes include dosage compensation, control over aberrant retrotransposon expression, and regulation of centromeric and telomeric heterochromatin [1] The importance of such processes is exemplified by the essential requirement for DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) in embryonic and early mammalian development [2,3]. Coincident with critical roles for DNA methyltransferases in the regulation of pluripotency, Fe(II)/a-ketoglutarate-dependent hydroxylation of 5-mC to 5-hydroxymethylcytosine (5-hmC) by Teneleven translocation (Tet) family proteins contributes to the maintenance of pluripotency [4,5,6] Discovery of this new epigenetic modification raises the possibility that 5-hmC could alter chromatin structure and thereby contribute to gene regulation. Despite the emergence of these important roles for Tet family proteins, and 5hmC-associated regulation in ES cells, the genomic- and chromatin-associated contexts of 5-hmC have gone unexplored in human embryonic stem cells
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