Limits...
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.

Show MeSH

Related in: MedlinePlus

A) Observed number of candidate enhancers in the regulatory domain of all genes compared to random expectation.The top ten observed genes are listed in Table 2. B,C) Heavily p300 occupied putative gene regulatory domains around Zfp608 and Mn1-Cryba4, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3757057&req=5

pgen-1003728-g004: A) Observed number of candidate enhancers in the regulatory domain of all genes compared to random expectation.The top ten observed genes are listed in Table 2. B,C) Heavily p300 occupied putative gene regulatory domains around Zfp608 and Mn1-Cryba4, respectively.

Mentions: The candidate enhancers we measured exhibit a tendency to cluster together, with some genes having tens of p300 peaks in their predicted regulatory domains. To determine what would be expected by chance, we randomly distributed the 6,629 peaks across the genome 1,000 times. In this random (which controls for gene regulatory domain length), we never observed any gene associated with more than 15 peaks (Figure 4A). In our true set, the most heavily regulated genes are associated with 20–42 peaks each. We can also use GREAT to rank all genes in the genome for the likelihood associated with the observed number of enhancers per gene vs. the length of the individual gene's regulatory domain (note that in this test, a gene with a smaller regulatory domain containing multiple enhancers, can rank higher than a gene with a much larger regulatory domain which contains more enhancers). When this variant of the GREAT test is run, the top ten most significant genes are the same ten genes with the absolute largest number of observed enhancers (p-value between 1.3×10−15 and 1.6×10−31). Three of these genes, Nfib, Sox4 and Sox11 are already known to play key roles in forebrain development. Three other genes, Zfp608 (Figure 4B), Auts2 and Tle3 have previously been noted for their specific neocortical expression patterns, though their roles in its development are not well understood. Intriguingly, two additional gene deserts, flanked by the gene pairs Mn1-Cryba4 (Figure 4C) and Gse1-Fam92b, all with unknown roles in neocortex development, are also packed with p300 elements (Table 2).


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)

A) Observed number of candidate enhancers in the regulatory domain of all genes compared to random expectation.The top ten observed genes are listed in Table 2. B,C) Heavily p300 occupied putative gene regulatory domains around Zfp608 and Mn1-Cryba4, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1003728-g004: A) Observed number of candidate enhancers in the regulatory domain of all genes compared to random expectation.The top ten observed genes are listed in Table 2. B,C) Heavily p300 occupied putative gene regulatory domains around Zfp608 and Mn1-Cryba4, respectively.
Mentions: The candidate enhancers we measured exhibit a tendency to cluster together, with some genes having tens of p300 peaks in their predicted regulatory domains. To determine what would be expected by chance, we randomly distributed the 6,629 peaks across the genome 1,000 times. In this random (which controls for gene regulatory domain length), we never observed any gene associated with more than 15 peaks (Figure 4A). In our true set, the most heavily regulated genes are associated with 20–42 peaks each. We can also use GREAT to rank all genes in the genome for the likelihood associated with the observed number of enhancers per gene vs. the length of the individual gene's regulatory domain (note that in this test, a gene with a smaller regulatory domain containing multiple enhancers, can rank higher than a gene with a much larger regulatory domain which contains more enhancers). When this variant of the GREAT test is run, the top ten most significant genes are the same ten genes with the absolute largest number of observed enhancers (p-value between 1.3×10−15 and 1.6×10−31). Three of these genes, Nfib, Sox4 and Sox11 are already known to play key roles in forebrain development. Three other genes, Zfp608 (Figure 4B), Auts2 and Tle3 have previously been noted for their specific neocortical expression patterns, though their roles in its development are not well understood. Intriguingly, two additional gene deserts, flanked by the gene pairs Mn1-Cryba4 (Figure 4C) and Gse1-Fam92b, all with unknown roles in neocortex development, are also packed with p300 elements (Table 2).

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