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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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Co-option of mobile elements as dorsal cerebral wall enhancers.Each p300 ChIP-seq set was overlapped with all interspersed repeat families. For each combination, the expected number of overlaps was determined using 10,000 simulations where the p300 set was randomly distributed across the genome and overlaps were counted.
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pgen-1003728-g006: Co-option of mobile elements as dorsal cerebral wall enhancers.Each p300 ChIP-seq set was overlapped with all interspersed repeat families. For each combination, the expected number of overlaps was determined using 10,000 simulations where the p300 set was randomly distributed across the genome and overlaps were counted.

Mentions: To determine if repetitive elements may have been co-opted as dorsal cerebral wall enhancers, we compared the overlap between our p300 set and all annotated interspersed repeat families in the UCSC genome browser. To control for the very different abundance of different repeat families, we shuffled our p300 set 10,000 times and noted the number of times the random sets overlapped each repeat family. For comparison, we repeated the same procedure with the four sets of previously obtained E11.5 p300 elements in forebrain, midbrain, limb and heart [9]. The most abundantly overlapping family of repeats with our E14.5 data is the MIRb family, which overlaps 238 p300 elements. This family has been noted before to be among the largest contributors to gene regulatory co-option among all mobile element families [30]. However, because many more copies of this repeat family are found in the genome, its fold enrichment of 1.84 against random overlaps is relatively low. In contrast, three poorly studied repeat families are found to make an extremely unlikely contribution to our p300 set: MER130, UCON31 and MER124. For the most enriched, MER130, 22 (24%) of 90 instances identified in the mouse genome overlap our E14.5 set, a 73 fold enrichment over expected (Figure 6).


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)

Co-option of mobile elements as dorsal cerebral wall enhancers.Each p300 ChIP-seq set was overlapped with all interspersed repeat families. For each combination, the expected number of overlaps was determined using 10,000 simulations where the p300 set was randomly distributed across the genome and overlaps were counted.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1003728-g006: Co-option of mobile elements as dorsal cerebral wall enhancers.Each p300 ChIP-seq set was overlapped with all interspersed repeat families. For each combination, the expected number of overlaps was determined using 10,000 simulations where the p300 set was randomly distributed across the genome and overlaps were counted.
Mentions: To determine if repetitive elements may have been co-opted as dorsal cerebral wall enhancers, we compared the overlap between our p300 set and all annotated interspersed repeat families in the UCSC genome browser. To control for the very different abundance of different repeat families, we shuffled our p300 set 10,000 times and noted the number of times the random sets overlapped each repeat family. For comparison, we repeated the same procedure with the four sets of previously obtained E11.5 p300 elements in forebrain, midbrain, limb and heart [9]. The most abundantly overlapping family of repeats with our E14.5 data is the MIRb family, which overlaps 238 p300 elements. This family has been noted before to be among the largest contributors to gene regulatory co-option among all mobile element families [30]. However, because many more copies of this repeat family are found in the genome, its fold enrichment of 1.84 against random overlaps is relatively low. In contrast, three poorly studied repeat families are found to make an extremely unlikely contribution to our p300 set: MER130, UCON31 and MER124. For the most enriched, MER130, 22 (24%) of 90 instances identified in the mouse genome overlap our E14.5 set, a 73 fold enrichment over expected (Figure 6).

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