title: Conserved role of intragenic DNA methylation in regulating alternative promoters.
abstract: Although it is known that the methylation of DNA in 5' promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear. In mammals, tissue- and cell type-specific methylation is present in a small percentage of 5' CpG island (CGI) promoters, whereas a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences. Tissue-specific intragenic methylation might reduce, or, paradoxically, enhance transcription elongation efficiency. Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes. To investigate the role of intragenic methylation, we generated a map of DNA methylation from the human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were shown to be in intragenic and intergenic regions, whereas less than 3% of CpG islands in 5' promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters. The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus and its mouse homologue demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue- and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.
authors.affiliation: Brain Tumor Research Center, Department of Neurosurgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA.
authors.forename: Alika K
authors.initials: AK
authors.lastname: Maunakea
authors.forename: Raman P
authors.initials: RP
authors.lastname: Nagarajan
authors.forename: Mikhail
authors.initials: M
authors.lastname: Bilenky
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Ballinger
authors.forename: Cletus
authors.initials: C
authors.lastname: D'Souza
authors.forename: Shaun D
authors.initials: SD
authors.lastname: Fouse
authors.forename: Brett E
authors.initials: BE
authors.lastname: Johnson
authors.forename: Chibo
authors.initials: C
authors.lastname: Hong
authors.forename: Cydney
authors.initials: C
authors.lastname: Nielsen
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
authors.forename: Allen
authors.initials: A
authors.lastname: Delaney
authors.forename: Richard
authors.initials: R
authors.lastname: Varhol
authors.forename: Nina
authors.initials: N
authors.lastname: Thiessen
authors.forename: Ksenya
authors.initials: K
authors.lastname: Shchors
authors.forename: Vivi M
authors.initials: VM
authors.lastname: Heine
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Xing
authors.forename: Chris
authors.initials: C
authors.lastname: Fiore
authors.forename: Maximiliaan
authors.initials: M
authors.lastname: Schillebeeckx
authors.forename: Steven J M
authors.initials: SJ
authors.lastname: Jones
authors.forename: David
authors.initials: D
authors.lastname: Haussler
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
authors.forename: Martin
authors.initials: M
authors.lastname: Hirst
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Costello
mesh_terms: D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000166:cytology / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics; D002460:Cell Line; D017124:Conserved Sequence / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D021901:DNA, Intergenic / Q000235:genetics / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D005786:Gene Expression Regulation; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins; D009928:Organ Specificity; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D021901:DNA, Intergenic; D006657:Histones; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C492357:SHANK3 protein, human; C492356:Shank3 protein, mouse