5-hydroxymethylcytosine is highly dynamic across human fetal brain development

Helen Spiers,Eilis Hannon,Leonard C. Schalkwyk,Jonathan Mill,Nicholas J. Bray

doi:10.1186/s12864-017-4091-x

Abstract

BackgroundEpigenetic processes play a key role in orchestrating transcriptional regulation during the development of the human central nervous system. We previously described dynamic changes in DNA methylation (5mC) occurring during human fetal brain development, but other epigenetic processes operating during this period have not been extensively explored. Of particular interest is DNA hydroxymethylation (5hmC), a modification that is enriched in the human brain and hypothesized to play an important role in neuronal function, learning and memory. In this study, we quantify 5hmC across the genome of 71 human fetal brain samples spanning 23 to 184 days post-conception.ResultsWe identify widespread changes in 5hmC occurring during human brain development, notable sex-differences in 5hmC in the fetal brain, and interactions between 5mC and 5hmC at specific sites. Finally, we identify loci where 5hmC in the fetal brain is associated with genetic variation.ConclusionsThis study represents the first systematic analysis of dynamic changes in 5hmC across human neurodevelopment and highlights the potential importance of this modification in the human brain. A searchable database of our fetal brain 5hmC data is available as a resource to the research community at http://www.epigenomicslab.com/online-data-resources.

Highlights

Epigenetic processes play a key role in orchestrating transcriptional regulation during the development of the human central nervous system
A quarter (n = 103,063 (25.64%)) of all autosomal probes included in the analysis were characterized by non-detectable 5hmC (i.e. ΔβBS-Oxidative bisulfite (oxBS) < 0.036) in all 71 fetal brain samples examined (Fig. 1a and Additional file 1: Table S1); these sites were significantly enriched in CpG islands and other promoter regulatory regions including the transcription start-site (TSS), 5’UTR and 1st Exon (Additional file 1: Table S2)
There are discrete modules of cohydroxymethylated loci associated with brain development that are significantly enriched for genes involved in neurodevelopmental processes

Summary

Introduction

Epigenetic processes play a key role in orchestrating transcriptional regulation during the development of the human central nervous system. We previously described dynamic changes in DNA methylation (5mC) occurring during human fetal brain development, but other epigenetic processes operating during this period have not been extensively explored. Of particular interest is DNA hydroxymethylation (5hmC), a modification that is enriched in the human brain and hypothesized to play an important role in neuronal function, learning and memory. Human brain development is characterized by coordinated changes in gene expression mediated by a complex interaction between transcription factors [1] and epigenetic processes [2]. We recently characterized the dramatic alterations in DNA methylation (5-methylcytosine, 5mC) occurring during human neurodevelopment [3], but little is known about the role of other epigenetic modifications during this period.

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