title: 5-hmC in the brain is abundant in synaptic genes and shows differences at the exon-intron boundary.
abstract: 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.
authors.affiliation: The Krembil Family Epigenetics Laboratory, The Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: Tarang
authors.initials: T
authors.lastname: Khare
authors.forename: Shraddha
authors.initials: S
authors.lastname: Pai
authors.forename: Karolis
authors.initials: K
authors.lastname: Koncevicius
authors.forename: Mrinal
authors.initials: M
authors.lastname: Pal
authors.forename: Edita
authors.initials: E
authors.lastname: Kriukiene
authors.forename: Zita
authors.initials: Z
authors.lastname: Liutkeviciute
authors.forename: Manuel
authors.initials: M
authors.lastname: Irimia
authors.forename: Peixin
authors.initials: P
authors.lastname: Jia
authors.forename: Carolyn
authors.initials: C
authors.lastname: Ptak
authors.forename: Menghang
authors.initials: M
authors.lastname: Xia
authors.forename: Raymond
authors.initials: R
authors.lastname: Tice
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tochigi
authors.forename: Solange
authors.initials: S
authors.lastname: Moréra
authors.forename: Anaies
authors.initials: A
authors.lastname: Nazarians
authors.forename: Denise
authors.initials: D
authors.lastname: Belsham
authors.forename: Albert H C
authors.initials: AH
authors.lastname: Wong
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
authors.forename: Sun Chong
authors.initials: SC
authors.lastname: Wang
authors.forename: Philipp
authors.initials: P
authors.lastname: Kapranov
authors.forename: Rafal
authors.initials: R
authors.lastname: Kustra
authors.forename: Viviane
authors.initials: V
authors.lastname: Labrie
authors.forename: Saulius
authors.initials: S
authors.lastname: Klimasauskas
authors.forename: Arturas
authors.initials: A
authors.lastname: Petronis
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D017398:Alternative Splicing; D000818:Animals; D001921:Brain / Q000502:physiology*; D002460:Cell Line; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D005964:Glucosyltransferases / Q000378:metabolism; D006801:Humans; D007438:Introns; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D009928:Organ Specificity; D012326:RNA Splicing; D015203:Reproducibility of Results; D013569:Synapses / Q000235:genetics* / Q000378:metabolism
chemical_list: C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; D005964:Glucosyltransferases