title: Epigenetic dysregulation in the developing Down syndrome cortex.
abstract: Using Illumina 450K arrays, 1.85% of all analyzed CpG sites were significantly hypermethylated and 0.31% hypomethylated in fetal Down syndrome (DS) cortex throughout the genome. The methylation changes on chromosome 21 appeared to be balanced between hypo- and hyper-methylation, whereas, consistent with prior reports, all other chromosomes showed 3-11 times more hyper- than hypo-methylated sites. Reduced NRSF/REST expression due to upregulation of DYRK1A (on chromosome 21q22.13) and methylation of REST binding sites during early developmental stages may contribute to this genome-wide excess of hypermethylated sites. Upregulation of DNMT3L (on chromosome 21q22.4) could lead to de novo methylation in neuroprogenitors, which then persists in the fetal DS brain where DNMT3A and DNMT3B become downregulated. The vast majority of differentially methylated promoters and genes was hypermethylated in DS and located outside chromosome 21, including the protocadherin gamma (PCDHG) cluster on chromosome 5q31, which is crucial for neural circuit formation in the developing brain. Bisulfite pyrosequencing and targeted RNA sequencing showed that several genes of PCDHG subfamilies A and B are hypermethylated and transcriptionally downregulated in fetal DS cortex. Decreased PCDHG expression is expected to reduce dendrite arborization and growth in cortical neurons. Since constitutive hypermethylation of PCDHG and other genes affects multiple tissues, including blood, it may provide useful biomarkers for DS brain development and pharmacologic targets for therapeutic interventions.
authors.affiliation: a Institute of Human Genetics, Julius Maximilians University , Würzburg , Germany.
authors.forename: Nady
authors.initials: N
authors.lastname: El Hajj
authors.affiliation: a Institute of Human Genetics, Julius Maximilians University , Würzburg , Germany.|b Department of Bioinformatics , Julius Maximilians University , Würzburg , Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Dittrich
authors.affiliation: a Institute of Human Genetics, Julius Maximilians University , Würzburg , Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Böck
authors.affiliation: c Center for Neuropathology and Prion Research , Ludwig Maximilians University , Munich , Germany.
authors.forename: Theo F J
authors.initials: TF
authors.lastname: Kraus
authors.affiliation: a Institute of Human Genetics, Julius Maximilians University , Würzburg , Germany.
authors.forename: Indrajit
authors.initials: I
authors.lastname: Nanda
authors.affiliation: b Department of Bioinformatics , Julius Maximilians University , Würzburg , Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Müller
authors.affiliation: d Department of Pathology , University Medical Center , Mainz , Germany.
authors.forename: Larissa
authors.initials: L
authors.lastname: Seidmann
authors.affiliation: e Rehabilitation Clinic for Children and Adolescents , Westerland/Sylt , Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Tralau
authors.affiliation: f Department of Radiation Oncology and Radiotherapy , University Medical Center , Mainz , Germany.
authors.forename: Danuta
authors.initials: D
authors.lastname: Galetzka
authors.affiliation: a Institute of Human Genetics, Julius Maximilians University , Würzburg , Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Schneider
authors.affiliation: a Institute of Human Genetics, Julius Maximilians University , Würzburg , Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Haaf
mesh_terms: D000328:Adult; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D004314:Down Syndrome / Q000235:genetics*; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D000071446:Neuronal Outgrowth; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D000097603:Dyrk Kinases
chemical_list: D015820:Cadherins; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C000717967:DNMT3A protein, human; C412484:DNMT3L protein, human
keywords: DNA methylation; Down syndrome; fetal brain development; frontal cortex; protocadherin gamma cluster