Abstract
BackgroundDNA methylation is an epigenetic mechanism essential for gene regulation and vital for mammalian development. 5-hydroxymethylcytosine (5hmC) is the first oxidative product of the TET-mediated 5-methylcytosine (5mC) demethylation pathway. Aside from being a key intermediate in cytosine demethylation, 5hmC may have potential regulatory functions with emerging importance in mammalian biology.MethodsHere, we investigate the global 5hmC enrichment in five brain structures, including cerebellum, cerebral cortex, hippocampus, hypothalamus and thalamus, as well as liver tissues from female and male adult mice by using chemical capture-based technique coupled with next-generation sequencing. At the same time, we carried out total RNA sequencing (RNA-seq) to analyze the transcriptomes of brain regions and liver tissues.ResultsOur results reveal preferential 5hmC enrichment in the gene bodies of expressed genes, and 5hmC levels of many protein-coding genes are positively correlated with RNA expression intensity. However, more than 75% of genes with low or no 5hmC enrichment are genes encode for mitochondrial proteins and ribosomal proteins despite being actively transcribed, implying different transcriptional regulation mechanisms of these housekeeping genes. Brain regions developed from the same embryonic structures have more similar 5hmC profiles. Also, the genic 5hmC enrichment pattern is highly tissue-specific, and 5hmC marks genes involving in tissue-specific biological processes. Sex chromosomes are mostly depleted of 5hmC, and the X inactive specific transcript (Xist) gene located on the X chromosome is the only gene to show sex-specific 5hmC enrichment.ConclusionsThis is the first report of the whole-genome 5hmC methylome of five major brain structures and liver tissues in mice of both sexes. This study offers a comprehensive resource for future work of mammalian cytosine methylation dynamics. Our findings offer additional evidence that suggests 5hmC is an active epigenetic mark stably maintained after the global reprogramming event during early embryonic development.
Highlights
Mammalian transcriptional regulation is complex and involves multiple layers of coordinated control mechanisms to ensure proper function at cellular and organismal levels
Our results reveal preferential 5hmC enrichment in the gene bodies of expressed genes, and 5hmC levels of many protein-coding genes are positively correlated with RNA expression intensity
The genic 5hmC enrichment pattern is highly tissue-specific, and 5hmC marks genes involving in tissue-specific biological processes
Summary
Mammalian transcriptional regulation is complex and involves multiple layers of coordinated control mechanisms to ensure proper function at cellular and organismal levels. [3,4] Other than transcriptional regulation, DNA methylation plays important roles in diverse biological processes, such as embryonic development, genomic imprinting, Xchromosome inactivation, differentiation and cancer development. Since the discovery of 5mC, multiple oxidized 5mC variants have been identified These variants are the products of sequentially oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5hmC to 5-formylcytosine (5fC), and 5fC to 5-carboxylcytosine (5caC) by TET family of cytosine oxygenases. [5,6,7] The DNA demethylation process plays an essential role in early embryogenesis. After fertilization, both maternal and paternal genomes are reprogrammed to totipotency. DNA methylation is an epigenetic mechanism essential for gene regulation and vital for mammalian development. Aside from being a key intermediate in cytosine demethylation, 5hmC may have potential regulatory functions with emerging importance in mammalian biology
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