5-hmC in the brain is abundant in synaptic genes and shows differences at the exon-intron boundary

Tarang Khare, Shraddha Pai, Karolis Koncevicius, Mrinal Pal, Edita Kriukiene, Zita Liutkeviciute, Manuel Irimia, Peixin Jia, Carolyn Ptak, Menghang Xia, Raymond Tice, Mamoru Tochigi, Solange Moréra, Anaies Nazarians, Denise Belsham, Albert H.C. Wong, Benjamin J. Blencowe, Sun Chong Wang, Philipp Kapranov, Rafal KustraViviane Labrie, Saulius Klimasauskas, Arturas Petronis

Research output: Contribution to journalArticlepeer-review

181 Scopus citations


The 5-methylcytosine (5-mC) derivative 5-hydroxymethylcytosine (5-hmC) is abundant in the brain for unknown reasons. Here we characterize the genomic distribution of 5-hmC and 5-mC in human and mouse tissues. We assayed 5-hmC by using glucosylation coupled with restriction-enzyme digestion and microarray analysis. We detected 5-hmC enrichment in genes with synapse-related functions in both human and mouse brain. We also identified substantial tissue-specific differential distributions of these DNA modifications at the exon-intron boundary in human and mouse. This boundary change was mainly due to 5-hmC in the brain but due to 5-mC in non-neural contexts. This pattern was replicated in multiple independent data sets and with single-molecule sequencing. Moreover, in human frontal cortex, constitutive exons contained higher levels of 5-hmC relative to alternatively spliced exons. Our study suggests a new role for 5-hmC in RNA splicing and synaptic function in the brain.

Original languageEnglish
Pages (from-to)1037-1044
Number of pages8
JournalNature Structural and Molecular Biology
Issue number10
StatePublished - Oct 2012


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