title: CpG sites with continuously increasing or decreasing methylation from early to late human fetal brain development.
abstract: Normal human brain development is dependent on highly dynamic epigenetic processes for spatial and temporal gene regulation. Recent work identified wide-spread changes in DNA methylation during fetal brain development. We profiled CpG methylation in frontal cortex of 27 fetuses from gestational weeks 12-42, using Illumina 450K methylation arrays. Sites showing genome-wide significant correlation with gestational age were compared to a publicly available data set from gestational weeks 3-26. Altogether, we identified 2016 matching developmentally regulated differentially methylated positions (m-dDMPs): 1767m-dDMPs were hypermethylated and 1149 hypomethylated during fetal development. M-dDMPs are underrepresented in CpG islands and gene promoters, and enriched in gene bodies. They appear to cluster in certain chromosome regions. M-dDMPs are significantly enriched in autism-associated genes and CpGs. Our results promote the idea that reduced methylation dynamics during fetal brain development may predispose to autism. In addition, m-dDMPs are enriched in genes with human-specific brain expression patterns and/or histone modifications. Collectively, we defined a subset of dDMPs exhibiting constant methylation changes from early to late pregnancy. The same epigenetic mechanisms involving methylation changes in cis-regulatory regions may have been adopted for human brain evolution and ontogeny.
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schneider
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany; Department of Bioinformatics, Julius Maximilians University, 97074 Würzburg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Dittrich
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Böck
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany.
authors.forename: Indrajit
authors.initials: I
authors.lastname: Nanda
authors.affiliation: Department of Bioinformatics, Julius Maximilians University, 97074 Würzburg, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.affiliation: Department of Pathology, University Medical Center, 55131 Mainz, Germany.
authors.forename: Larissa
authors.initials: L
authors.lastname: Seidmann
authors.affiliation: Department of Pathology, University Medical Center, 55131 Mainz, Germany; Rehabilitation Clinic for Children and Adolescents, 25980 Westerland/Sylt, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Tralau
authors.affiliation: Department of Radiation Oncology and Radiotherapy, University Medical Center, 55131 Mainz, Germany.
authors.forename: Danuta
authors.initials: D
authors.lastname: Galetzka
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany.
authors.forename: Nady
authors.initials: N
authors.lastname: El Hajj
authors.affiliation: Institute of Human Genetics, Julius Maximilians University, 97074 Würzburg, Germany. Electronic address: thomas.haaf@uni-wuerzburg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haaf
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D001921:Brain / Q000196:embryology / Q000378:metabolism*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male
keywords: Autism; DNA methylation dynamics; Fetal brain development; Frontal cortex; Methylome