A potential role for 5hmC in RNA splicing and synaptic function in the brain
5-methylcytosine (5-mC) is an epigenetic modification of DNA that is essential for normal development and is associated with a number of key cellular processes including genomic imprinting, X-chromosome inactivation, suppression of repetitive elements, and carcinogenesis. 5-mC can be further modified in cells to 5-hydroxymethylcytosine (5-hmC) through oxidization. This novel epigenetic mark has been widely studied in different tissues and different species in the last couple of years. 5-hmC is particularly enriched in the brain compared with other tissues, and it was also found to be related to certain types of tumors. While the exact function of this epigenetic modification is still not fully understood, a recent paper published by Khare et al. in Nat Struc. & Mol. Bio. may shed some light on it. An international research team led by Kilassauskas and Petronis developed a 5-hmC assay which employs glucosylation coupled with restriction enzyme digestion and microarray analysis. This assay is able to map 5-hmC at up to single CpG resolution. Using this assay, the authors mapped both 5-mC and 5-hmC in a variety of neuronal and non-neuronal tissues from both humans and mice.
Through functional genome annotation analysis, they found 5-hmC was statistically enriched in genes related to neuronal synaptic plasticity. In particular, 5-hmC modifications were found to be clustered in several groups of genes which are involved in distinct aspects of synaptic remodeling such as ion channels, members of the Rho GTPase signaling pathway, and axon-guidance molecules. Furthermore, the products of most genes with high levels of 5-hmC are functionally located at the plasma membrane, rather than being cytosolic. It was also found that 5-hmC levels at exon-intron boundaries were high in neuronal tissues, suggesting that 5-hmC may affect the process of pre-mRNA splicing in addition to transcriptional regulation. Further studies are needed to elucidate this observation, as transcription and splicing may also affect epigenetic DNA modifications, and mechanisms for cross-talk likely exist between epigenetic regulation, splicing and transcription.
Khare et al. (2012) 5-hmC in the brain is abundant in synaptic genes and shows differences at the exon-intron boundary. Nat Struc. & Mol. Bio. 2012 Sep 9. doi: 10.1038/nsmb.2372. [Epub ahead of print]
Link to article: http://www.nature.com/nsmb/journal/vaop/ncurrent/full/nsmb.2372.html