title: The enhancer landscape during early neocortical development reveals patterns of dense regulation and co-option.
abstract: Genetic studies have identified a core set of transcription factors and target genes that control the development of the neocortex, the region of the human brain responsible for higher cognition. The specific regulatory interactions between these factors, many key upstream and downstream genes, and the enhancers that mediate all these interactions remain mostly uncharacterized. We perform p300 ChIP-seq to identify over 6,600 candidate enhancers active in the dorsal cerebral wall of embryonic day 14.5 (E14.5) mice. Over 95% of the peaks we measure are conserved to human. Eight of ten (80%) candidates tested using mouse transgenesis drive activity in restricted laminar patterns within the neocortex. GREAT based computational analysis reveals highly significant correlation with genes expressed at E14.5 in key areas for neocortex development, and allows the grouping of enhancers by known biological functions and pathways for further studies. We find that multiple genes are flanked by dozens of candidate enhancers each, including well-known key neocortical genes as well as suspected and novel genes. Nearly a quarter of our candidate enhancers are conserved well beyond mammals. Human and zebrafish regions orthologous to our candidate enhancers are shown to most often function in other aspects of central nervous system development. Finally, we find strong evidence that specific interspersed repeat families have contributed potentially key developmental enhancers via co-option. Our analysis expands the methodologies available for extracting the richness of information found in genome-wide functional maps.
authors.affiliation: Department of Computer Science, Stanford University, Stanford, California, United States of America.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Wenger
authors.forename: Shoa L
authors.initials: SL
authors.lastname: Clarke
authors.forename: James H
authors.initials: JH
authors.lastname: Notwell
authors.forename: Tisha
authors.initials: T
authors.lastname: Chung
authors.forename: Geetu
authors.initials: G
authors.lastname: Tuteja
authors.forename: Harendra
authors.initials: H
authors.lastname: Guturu
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Schaar
authors.forename: Gill
authors.initials: G
authors.lastname: Bejerano
mesh_terms: D000818:Animals; D001483:Base Sequence; D017124:Conserved Sequence / Q000235:genetics; D004742:Enhancer Elements, Genetic; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D019579:Neocortex / Q000254:growth & development* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development
chemical_list: D014157:Transcription Factors