Abstract
Background5-Hydroxymethylcytosine (5hmC) is an oxidation product of 5-methylcytosine (5mC), and adjacent CpG sites in mammalian genome can be co-methylated and co-hydroxymethylated due to the processivity of DNMT and TET enzymes.ResultsWe applied TAB-seq and oxBS-seq to selectively detect 5hmC and 5mC at base resolution in the mouse cortex, olfactory bulb and cerebellum tissues. We found that majority of the called 5hmC CpG sites frequently have 5mC modification simultaneously and are enriched in gene body regions of neuron development-related genes in brain tissues. Strikingly, by a systematic search of regions that show highly coordinated methylation and hydroxymethylation (MHBs and hMHBs), we found that MHBs significantly overlapped with hMHBs in gene body regions. Moreover, using a metric called methylation haplotype load, we defined a subset of 1361 tissue-specific MHBs and 3818 shared MHBs. Shared MHBs with low MHL correspond with developmental enhancers, and tissue-specific MHBs resemble the regulatory elements for tissue identity.ConclusionsOur results provide new insights into the role of coordinately oxidized 5mC to 5hmC as distal regulatory elements may involve in regulating tissue identity.
Highlights
The oxidation of 5mC to 5hmC is carried out by the 10–11 translocation (TET) enzymes [1]
Our results supported that a prominent role of coordinately oxidized 5mC to 5hmC as distal regulatory elements may involve in regulating tissue identity
Oxidization of 5mC to 5hmC but not global cytosine modification level characterizes brain tissues Firstly, we performed TAB-seq and oxBS-seq on cerebellum, cortex and olfactory bulb tissues derived from female mice
Summary
The oxidation of 5mC to 5hmC is carried out by the 10–11 translocation (TET) enzymes [1]. 5hmC is cell-type specific and the pattern can be harnessed for analyzing heterogeneous samples. The small differences at single-CpG site between tissue types which could be important markers for small subpopulations in these tissues will be within the error range of the TAB-seq (TET-assisted bisulfite sequencing) method [6]. Recent study has demonstrated superior sensitivity in detecting tissue-specific pattern with consideration of coordinated methylation of neighboring CpGs [7]. Due to the locally coordinated activities of DNMT and TET dioxygenase proteins, adjacent CpG sites on the same DNA molecule can share similar methylation and hydroxymethylation statuses. The analysis of CpG co-methylation and co-hydroxymethylation in cell
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