title: Developmental regulation of human cortex transcription and its clinical relevance at single base resolution.
abstract: Transcriptome analysis of human brain provides fundamental insight into development and disease, but it largely relies on existing annotation. We sequenced transcriptomes of 72 prefrontal cortex samples across six life stages and identified 50,650 differentially expression regions (DERs) associated with developmental and aging, agnostic of annotation. While many DERs annotated to non-exonic sequence (41.1%), most were similarly regulated in cytosolic mRNA extracted from independent samples. The DERs were developmentally conserved across 16 brain regions and in the developing mouse cortex, and were expressed in diverse cell and tissue types. The DERs were further enriched for active chromatin marks and clinical risk for neurodevelopmental disorders such as schizophrenia. Lastly, we demonstrate quantitatively that these DERs associate with a changing neuronal phenotype related to differentiation and maturation. These data show conserved molecular signatures of transcriptional dynamics across brain development, have potential clinical relevance and highlight the incomplete annotation of the human brain transcriptome.
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore MD 21205.|Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore MD 21205.|Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore MD 21205.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Jaffe
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore MD 21205.
authors.forename: Jooheon
authors.initials: J
authors.lastname: Shin
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore MD 21205.|Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore MD 21205.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Collado-Torres
authors.affiliation: Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore MD 21205.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore MD 21205.
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Leek
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore MD 21205.
authors.forename: Ran
authors.initials: R
authors.lastname: Tao
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore MD 21205.
authors.forename: Chao
authors.initials: C
authors.lastname: Li
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore MD 21205.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore MD 21205.
authors.forename: Yankai
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore MD 21205.|Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore MD 21205.|Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore MD 21205.
authors.forename: Brady J
authors.initials: BJ
authors.lastname: Maher
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore MD 21205.|Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore MD 21205.|Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore MD 21205.|Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205.|Department of Biological Sciences, Johns Hopkins School of Medicine, Baltimore, MD.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Hyde
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore MD 21205.
authors.forename: Joel E
authors.initials: JE
authors.lastname: Kleinman
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore MD 21205.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore MD 21205.|Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore MD 21205.|Department of Neuroscience, Johns Hopkins School of Medicine, Baltimore MD 21205.|Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D002540:Cerebral Cortex / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism*; D002843:Chromatin / Q000235:genetics; D017124:Conserved Sequence; D005260:Female; D005333:Fetus / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051379:Mice; D009474:Neurons / Q000502:physiology; D011247:Pregnancy; D059467:Transcriptome / Q000502:physiology*
chemical_list: D002843:Chromatin