title: Methylomic trajectories across human fetal brain development.
abstract: Epigenetic processes play a key role in orchestrating transcriptional regulation during development. The importance of DNA methylation in fetal brain development is highlighted by the dynamic expression of de novo DNA methyltransferases during the perinatal period and neurodevelopmental deficits associated with mutations in the methyl-CpG binding protein 2 (MECP2) gene. However, our knowledge about the temporal changes to the epigenome during fetal brain development has, to date, been limited. We quantified genome-wide patterns of DNA methylation at ∼ 400,000 sites in 179 human fetal brain samples (100 male, 79 female) spanning 23 to 184 d post-conception. We identified highly significant changes in DNA methylation across fetal brain development at >7% of sites, with an enrichment of loci becoming hypomethylated with fetal age. Sites associated with developmental changes in DNA methylation during fetal brain development were significantly underrepresented in promoter regulatory regions but significantly overrepresented in regions flanking CpG islands (shores and shelves) and gene bodies. Highly significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small number of regions showing sex-specific DNA methylation trajectories across brain development. Weighted gene comethylation network analysis (WGCNA) revealed discrete modules of comethylated loci associated with fetal age that are significantly enriched for genes involved in neurodevelopmental processes. This is, to our knowledge, the most extensive study of DNA methylation across human fetal brain development to date, confirming the prenatal period as a time of considerable epigenomic plasticity.
authors: Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, United Kingdom;
authors: Helen
authors: H
authors: Spiers
authors: University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, United Kingdom;
authors: Eilis
authors: E
authors: Hannon
authors: School of Biological Sciences, University of Essex, Colchester CO4 3SQ, United Kingdom;
authors: Leonard C
authors: LC
authors: Schalkwyk
authors: Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, United Kingdom;
authors: Rebecca
authors: R
authors: Smith
authors: Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, United Kingdom;
authors: Chloe C Y
authors: CC
authors: Wong
authors: MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff CF24 4HQ, United Kingdom.
authors: Michael C
authors: MC
authors: O'Donovan
authors: Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, United Kingdom;
authors: Nicholas J
authors: NJ
authors: Bray
authors: Institute of Psychiatry, Psychology & Neuroscience, King's College London, London SE5 8AF, United Kingdom; University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, United Kingdom; j.mill@exeter.ac.uk.
authors: Jonathan
authors: J
authors: Mill
mesh_terms: D001321:Autistic Disorder / Q000235:genetics; D001482:Base Composition; D001921:Brain / Q000196:embryology* / Q000378:metabolism*; D016000:Cluster Analysis; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics / Q000379:methods; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D038081:Organogenesis / Q000235:genetics*; D011247:Pregnancy; D012045:Regulatory Sequences, Nucleic Acid; D012559:Schizophrenia / Q000235:genetics; D012737:Sex Factors
references: Genomics. 2009 Mar;93(3):213-20
references: 19059335
references: Annu Rev Cell Dev Biol. 2011;27:631-52
references: 21721946
references: Learn Mem. 2013;20(2):61-74
references: 23322554
references: Nat Biotechnol. 2009 Apr;27(4):361-8
references: 19329998
references: Curr Opin Neurol. 2013 Apr;26(2):146-53
references: 23406909
references: Science. 2012 Dec 21;338(6114):1619-22
references: 23160955
references: J Neurosci Res. 2005 Mar 15;79(6):734-46
references: 15672446
references: Bioinformatics. 2012 Nov 15;28(22):2986-8
references: 22954632
references: Mol Autism. 2013 Oct 03;4(1):36
references: 24090431
references: Lancet. 1995 Aug 26;346(8974):552-7
references: 7544856
references: J Neurosci. 2010 Mar 3;30(9):3489-98
references: 20203209
references: Nature. 2011 Oct 27;478(7370):483-9
references: 22031440
references: Nature. 2014 Jul 24;511(7510):421-7
references: 25056061
references: Science. 2013 Aug 9;341(6146):1237905
references: 23828890
references: Am J Hum Genet. 2012 Feb 10;90(2):260-72
references: 22305529
references: Genome Biol. 2013;14(10):R115
references: 24138928
references: Nature. 2011 Oct 27;478(7370):519-23
references: 22031444
references: Nat Rev Genet. 2014 Oct;15(10):647-61
references: 25159599
references: Nat Struct Mol Biol. 2012 Oct;19(10):1037-43
references: 22961382
references: Mol Endocrinol. 2004 Sep;18(9):2333-43
references: 15192074
references: BMC Genomics. 2013;14:293
references: 23631413
references: Nature. 2012 Jun 14;486(7402):256-60
references: 22699619
references: J Forensic Sci. 1994 Nov;39(6):1356-9
references: 7815018
references: Trends Genet. 1997 Aug;13(8):293-5
references: 9260513
references: Nat Rev Genet. 2013 Mar;14(3):204-20
references: 23400093
references: Nat Neurosci. 2010 Nov;13(11):1338-44
references: 20975758
references: Nucleic Acids Res. 2014 Jan;42(Database issue):D749-55
references: 24316576
references: Nat Neurosci. 2014 Mar;17(3):377-82
references: 24531307
references: Nature. 2010 Jul 8;466(7303):253-7
references: 20613842
references: Am J Hum Genet. 2008 Mar;82(3):696-711
references: 18319075
references: J Neuroendocrinol. 2010 Jul;22(7):728-35
references: 20456606
references: Neuron. 2009 May 28;62(4):494-509
references: 19477152
references: J Neuroendocrinol. 2011 Apr;23(4):355-64
references: 21251092
references: Nature. 2012 Sep 6;489(7414):57-74
references: 22955616
references: Mol Psychiatry. 2014 Aug;19(8):862-71
references: 23999529
references: Epigenetics Chromatin. 2013 Mar 03;6(1):4
references: 23452981
references: Hum Mol Genet. 2014 Mar 1;23(5):1260-70
references: 24163133
references: PLoS One. 2010;5(12):e15367
references: 21203455
references: J Genet Psychol. 1989 Mar;150(1):101-12
references: 2496195
references: Science. 2012 May 18;336(6083):934-7
references: 22539555
references: Genome Biol. 2014;15(10):483
references: 25347937
references: Nucleic Acids Res. 2009 Jan;37(Database issue):D832-6
references: 19015121
references: PLoS One. 2010;5(1):e8888
references: 20126651
references: Neuron. 2008 Dec 26;60(6):961-74
references: 19109904
references: Nat Rev Neurosci. 2010 Jun;11(6):377-88
references: 20485363
references: Nature. 2012 May 10;485(7397):237-41
references: 22495306
references: Nature. 2012 May 10;485(7397):242-5
references: 22495311
references: Nature. 2012 May 10;485(7397):246-50
references: 22495309
references: Nat Med. 2012 Aug;18(8):1194-204
references: 22869198
references: Science. 2005 Nov 4;310(5749):819-23
references: 16272115
references: Genes Dev. 2011 May 15;25(10):1010-22
references: 21576262
references: Curr Opin Neurobiol. 2007 Feb;17(1):103-11
references: 17275283
references: Nat Neurosci. 2011 Oct;14(10):1345-51
references: 21874013
references: Nature. 2008 Nov 27;456(7221):470-6
references: 18978772
references: Nature. 2007 May 24;447(7143):425-32
references: 17522676
references: Schizophr Bull. 2009 May;35(3):528-48
references: 19223657
references: Nature. 2013 Aug 22;500(7463):477-81
references: 23925113
references: J Neurosci. 2012 Jan 11;32(2):436-51
references: 22238080
references: Nature. 2009 Nov 19;462(7271):315-22
references: 19829295
references: Nat Rev Neurosci. 2006 Feb;7(2):93-102
references: 16429119
references: Genome Res. 2010 Jul;20(7):883-9
references: 20418490
references: Cell. 2013 Nov 21;155(5):997-1007
references: 24267886
references: Prog Neurobiol. 2005 Sep-Oct;77(1-2):128-38
references: 16243425
references: Biol Sex Differ. 2014 Jun 13;5:8
references: 24976947
references: Epigenetics. 2013 Feb;8(2):203-9
references: 23314698
references: Cell Res. 2013 Nov;23(11):1256-69
references: 23938295
references: Mech Dev. 2001 Dec;109(2):395-7
references: 11731256
references: Science. 2012 Sep 7;337(6099):1190-5
references: 22955828
references: Epigenetics Chromatin. 2013 Aug 06;6(1):26
references: 23919675
references: BMC Bioinformatics. 2008;9:559
references: 19114008
references: Nat Genet. 2003 Mar;33 Suppl:245-54
references: 12610534
references: Nat Genet. 2000 May;25(1):25-9
references: 10802651
references: Mol Reprod Dev. 2010 Feb;77(2):105-13
references: 19921744
references: Dev Neurobiol. 2014 Feb;74(2):113-22
references: 24124131
references: Dev Biol. 2009 Aug 15;332(2):339-50
references: 19501584
references: Front Endocrinol (Lausanne). 2011 Aug 11;2:21
references: 22654797
references: Nat Rev Genet. 2012 Jul;13(7):484-92
references: 22641018
references: Nat Neurosci. 2010 Nov;13(11):1319-23
references: 20975755