Abstract
5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark that regulates gene expression. Charting the landscape of 5hmC in human tissues is fundamental to understanding its regulatory functions. Here, we systematically profiled the whole-genome 5hmC landscape at single-base resolution for 19 types of human tissues. We found that 5hmC preferentially decorates gene bodies and outperforms gene body 5mC in reflecting gene expression. Approximately one-third of 5hmC peaks are tissue-specific differentially-hydroxymethylated regions (tsDhMRs), which are deposited in regions that potentially regulate the expression of nearby tissue-specific functional genes. In addition, tsDhMRs are enriched with tissue-specific transcription factors and may rewire tissue-specific gene expression networks. Moreover, tsDhMRs are associated with single-nucleotide polymorphisms identified by genome-wide association studies and are linked to tissue-specific phenotypes and diseases. Collectively, our results show the tissue-specific 5hmC landscape of the human genome and demonstrate that 5hmC serves as a fundamental regulatory element affecting tissue-specific gene expression programs and functions.
Highlights
5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark that regulates gene expression
Further studies found that the ten-eleven translocation (TET) family of Fe(II)- and α-ketoglutaratedependent DNA dioxygenases catalyzes the sequential oxidation of 5mC to 5hmC, 5formylcytosine (5fC) and 5-carboxylcytosine (5caC)[4,5,6]
We found that more than half of the tissue-specific differentially-hydroxymethylated regions (tsDhMRs) overlapped with at least one transcription factor-binding site (TFBS) (Supplementary Fig. 6a), and 20.1% of the distal tsDhMRs even overlapped with a b
Summary
We present a base-resolution atlas of 5hmC in human tissues. Hundreds of thousands of 5hmC peaks and millions of 5hmC sites were identified in this dataset, expanding the epigenomic landscape determined by previous large-scale efforts, for example, the ENCODE project. This study has enabled additional findings: (1) The correlation between 5hmC/5mC levels and gene expression in multiple human tissues has not been directly compared previously. We found that tissue- expressed genes show tissue-specific 5hmC patterns, which is not observed for 5mC; (2) tsDhMRs reside in regions with regulatory potential to control the expression of nearby tissue-specific functional genes; (3) tsDhMRs are enriched with tissue-specific transcription factorbinding sites and rewire the regulatory network of tissue-specific transcription factors; (4) tsDhMRs reside in regulatory elements that associate with tissue-related functional GWAS SNPs. Our 5hmC tissue map is base-resolution, owning to the use of hmC-CATCH21. The gene body 5hmC levels may be used to infer gene expression in tissues. Tissue-specific TFs are enriched in tsDhMRs, providing a mechanism by which key TFs may regulate tissue-specific gene expression via tsDhMRs. Based on our identified tsDhMRs, future studies could be designed to illustrate the specific mechanisms by which 5hmC can regulate tissue development and differentiation. Expression Level (TPM) rs4489968 rs7172038 rs7183206 heart rate atrial fibrillation atrial fibrillation
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