Distal regulatory elements identified by methylation and hydroxymethylation haplotype blocks from mouse brain

Area of Science:

• Epigenetics
• Genomics
• Molecular Biology

Background:

• 5-Hydroxymethylcytosine (5hmC) is an oxidation product of 5-methylcytosine (5mC).
• Adjacent CpG sites in the mammalian genome can be co-methylated and co-hydroxymethylated.
• Enzyme processivity of DNMT and TET influences co-modification patterns.

Purpose of the Study:

• To selectively detect 5hmC and 5mC at base resolution in mouse brain tissues.
• To investigate the co-occurrence and genomic distribution of 5hmC and 5mC.
• To identify and characterize coordinated methylation and hydroxymethylation regions (MHBs).

Main Methods:

• Application of TAB-seq and oxBS-seq for base-resolution detection of 5hmC and 5mC.
• Analysis of mouse cortex, olfactory bulb, and cerebellum tissues.
• Systematic search for regions with highly coordinated methylation and hydroxymethylation (MHBs and hMHBs).
• Utilized methylation haplotype load (MHL) to define tissue-specific and shared MHBs.

Main Results:

• Majority of 5hmC CpG sites co-occur with 5mC modification.
• These co-modified sites are enriched in gene bodies of neuron development-related genes.
• MHBs significantly overlap with hMHBs in gene body regions.
• Identified 1361 tissue-specific MHBs and 3818 shared MHBs using MHL.
• Shared MHBs with low MHL correlate with developmental enhancers.
• Tissue-specific MHBs resemble regulatory elements for tissue identity.

Conclusions:

• Coordinately oxidized 5mC to 5hmC modifications provide new insights into epigenetic regulation.
• These regions may function as distal regulatory elements involved in maintaining tissue identity.