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The enhancer landscape during early neocortical development reveals patterns of dense regulation and co-option.

Wenger AM, Clarke SL, Notwell JH, Chung T, Tuteja G, Guturu H, Schaar BT, Bejerano G - PLoS Genet. (2013)

Bottom Line: 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.Finally, we find strong evidence that specific interspersed repeat families have contributed potentially key developmental enhancers via co-option.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science, Stanford University, Stanford, California, United States of America.

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.

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Monomer and dimer transcription factor motif predictions most enriched in the E14.5 p300 ChIP-seq set.Motif fold enrichment is relative to length and GC-matched regions of the mouse genome.
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pgen-1003728-g003: Monomer and dimer transcription factor motif predictions most enriched in the E14.5 p300 ChIP-seq set.Motif fold enrichment is relative to length and GC-matched regions of the mouse genome.

Mentions: We identified a number of distinct enriched motifs, most of which belong to known important regulators of neocortex development (Figure 3). The Neurod/Neurog (2,452/6,629 enhancers = 37%; fold: 2.39), Lhx/Lmx (2,129 = 32%; fold: 2.42), Nfi (325 = 5%; fold: 4.14), and Rfx dimer (195 = 3%; fold: 3.33) motifs are all highly enriched in the candidate p300 enhancers. Factors from all four families have known roles in mammalian brain development [7], [19]–[21]. We also discovered two novel motifs enriched in the set: an alternative configuration from the known Nfi dimer motif [22] (379 = 6%; fold: 2.06) and a novel Hox dimer motif (473 = 7%; fold: 2.32).


The enhancer landscape during early neocortical development reveals patterns of dense regulation and co-option.

Wenger AM, Clarke SL, Notwell JH, Chung T, Tuteja G, Guturu H, Schaar BT, Bejerano G - PLoS Genet. (2013)

Monomer and dimer transcription factor motif predictions most enriched in the E14.5 p300 ChIP-seq set.Motif fold enrichment is relative to length and GC-matched regions of the mouse genome.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757057&req=5

pgen-1003728-g003: Monomer and dimer transcription factor motif predictions most enriched in the E14.5 p300 ChIP-seq set.Motif fold enrichment is relative to length and GC-matched regions of the mouse genome.
Mentions: We identified a number of distinct enriched motifs, most of which belong to known important regulators of neocortex development (Figure 3). The Neurod/Neurog (2,452/6,629 enhancers = 37%; fold: 2.39), Lhx/Lmx (2,129 = 32%; fold: 2.42), Nfi (325 = 5%; fold: 4.14), and Rfx dimer (195 = 3%; fold: 3.33) motifs are all highly enriched in the candidate p300 enhancers. Factors from all four families have known roles in mammalian brain development [7], [19]–[21]. We also discovered two novel motifs enriched in the set: an alternative configuration from the known Nfi dimer motif [22] (379 = 6%; fold: 2.06) and a novel Hox dimer motif (473 = 7%; fold: 2.32).

Bottom Line: 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.Finally, we find strong evidence that specific interspersed repeat families have contributed potentially key developmental enhancers via co-option.

View Article: PubMed Central - PubMed

Affiliation: Department of Computer Science, Stanford University, Stanford, California, United States of America.

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.

Show MeSH
Related in: MedlinePlus