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Gene regulatory networks in neural cell fate acquisition from genome-wide chromatin association of Geminin and Zic1

View Article: PubMed Central - PubMed

ABSTRACT

Neural cell fate acquisition is mediated by transcription factors expressed in nascent neuroectoderm, including Geminin and members of the Zic transcription factor family. However, regulatory networks through which this occurs are not well defined. Here, we identified Geminin-associated chromatin locations in embryonic stem cells and Geminin- and Zic1-associated locations during neural fate acquisition at a genome-wide level. We determined how Geminin deficiency affected histone acetylation at gene promoters during this process. We integrated these data to demonstrate that Geminin associates with and promotes histone acetylation at neurodevelopmental genes, while Geminin and Zic1 bind a shared gene subset. Geminin- and Zic1-associated genes exhibit embryonic nervous system-enriched expression and encode other regulators of neural development. Both Geminin and Zic1-associated peaks are enriched for Zic1 consensus binding motifs, while Zic1-bound peaks are also enriched for Sox3 motifs, suggesting co-regulatory potential. Accordingly, we found that Geminin and Zic1 could cooperatively activate the expression of several shared targets encoding transcription factors that control neurogenesis, neural plate patterning, and neuronal differentiation. We used these data to construct gene regulatory networks underlying neural fate acquisition. Establishment of this molecular program in nascent neuroectoderm directly links early neural cell fate acquisition with regulatory control of later neurodevelopment.

No MeSH data available.


Enrichment of transcription factor consensus binding motifs in Gmnn- and Zic1-associated sequences in NE.(A) Gmnn-associated or (B) Zic1-associated peak sequences in NE were used to obtain the most highly enriched transcription factor consensus binding motifs. (C) Relative enrichment in ES cells and in embryonic-adult CNS was defined for Gmnn and Zic1, and for the transcription factors that associate with the consensus motifs in (A,B), with expression trends summarized in (D). (E) Associations between these transcription factors, as defined by these ChIP-seq data and Sox3 ChIP-seq analysis in ES-derived NE35. (F,G) Gmnn- and Zic1-associated transcription factors exhibit embryonic CNS enriched expression and include those with known roles in neural development.
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f7: Enrichment of transcription factor consensus binding motifs in Gmnn- and Zic1-associated sequences in NE.(A) Gmnn-associated or (B) Zic1-associated peak sequences in NE were used to obtain the most highly enriched transcription factor consensus binding motifs. (C) Relative enrichment in ES cells and in embryonic-adult CNS was defined for Gmnn and Zic1, and for the transcription factors that associate with the consensus motifs in (A,B), with expression trends summarized in (D). (E) Associations between these transcription factors, as defined by these ChIP-seq data and Sox3 ChIP-seq analysis in ES-derived NE35. (F,G) Gmnn- and Zic1-associated transcription factors exhibit embryonic CNS enriched expression and include those with known roles in neural development.

Mentions: To consider how Geminin and Zic1 may associate with the genome during neural fate acquisition, we examined sequence motifs enriched at their associated peaks in NE. Both Gmnn and Zic1 peaks in NE were enriched for Zic1 consensus binding sequence motifs, suggesting potential locations for Gmnn/Zic1 cooperative action in NE gene regulation (Fig. 7A,B). Gmnn-bound peaks in NE were also enriched for consensus binding motifs for two homeodomain transcription factors, Six6 and the Iroquois transcription factor Irx2 (Fig. 7A). Gmnn interactions have been described with homeodomain transcription factors, including several Hox transcription factors and Six3/Six6151731. As both Irx2 and Six6 control regional neural plate patterning323334, these or other homeodomain transcription factors that bind to these consensus motifs could potentially modulate Gmnn’s activity at these locations. Both Gmnn and Zic1-associated peaks also contain consensus motifs for Sox17, while Zic1 NE peaks were also enriched for consensus binding sequence motifs for Sox3 and Mef2c (Fig. 7A,B).


Gene regulatory networks in neural cell fate acquisition from genome-wide chromatin association of Geminin and Zic1
Enrichment of transcription factor consensus binding motifs in Gmnn- and Zic1-associated sequences in NE.(A) Gmnn-associated or (B) Zic1-associated peak sequences in NE were used to obtain the most highly enriched transcription factor consensus binding motifs. (C) Relative enrichment in ES cells and in embryonic-adult CNS was defined for Gmnn and Zic1, and for the transcription factors that associate with the consensus motifs in (A,B), with expression trends summarized in (D). (E) Associations between these transcription factors, as defined by these ChIP-seq data and Sox3 ChIP-seq analysis in ES-derived NE35. (F,G) Gmnn- and Zic1-associated transcription factors exhibit embryonic CNS enriched expression and include those with known roles in neural development.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC5121602&req=5

f7: Enrichment of transcription factor consensus binding motifs in Gmnn- and Zic1-associated sequences in NE.(A) Gmnn-associated or (B) Zic1-associated peak sequences in NE were used to obtain the most highly enriched transcription factor consensus binding motifs. (C) Relative enrichment in ES cells and in embryonic-adult CNS was defined for Gmnn and Zic1, and for the transcription factors that associate with the consensus motifs in (A,B), with expression trends summarized in (D). (E) Associations between these transcription factors, as defined by these ChIP-seq data and Sox3 ChIP-seq analysis in ES-derived NE35. (F,G) Gmnn- and Zic1-associated transcription factors exhibit embryonic CNS enriched expression and include those with known roles in neural development.
Mentions: To consider how Geminin and Zic1 may associate with the genome during neural fate acquisition, we examined sequence motifs enriched at their associated peaks in NE. Both Gmnn and Zic1 peaks in NE were enriched for Zic1 consensus binding sequence motifs, suggesting potential locations for Gmnn/Zic1 cooperative action in NE gene regulation (Fig. 7A,B). Gmnn-bound peaks in NE were also enriched for consensus binding motifs for two homeodomain transcription factors, Six6 and the Iroquois transcription factor Irx2 (Fig. 7A). Gmnn interactions have been described with homeodomain transcription factors, including several Hox transcription factors and Six3/Six6151731. As both Irx2 and Six6 control regional neural plate patterning323334, these or other homeodomain transcription factors that bind to these consensus motifs could potentially modulate Gmnn’s activity at these locations. Both Gmnn and Zic1-associated peaks also contain consensus motifs for Sox17, while Zic1 NE peaks were also enriched for consensus binding sequence motifs for Sox3 and Mef2c (Fig. 7A,B).

View Article: PubMed Central - PubMed

ABSTRACT

Neural cell fate acquisition is mediated by transcription factors expressed in nascent neuroectoderm, including Geminin and members of the Zic transcription factor family. However, regulatory networks through which this occurs are not well defined. Here, we identified Geminin-associated chromatin locations in embryonic stem cells and Geminin- and Zic1-associated locations during neural fate acquisition at a genome-wide level. We determined how Geminin deficiency affected histone acetylation at gene promoters during this process. We integrated these data to demonstrate that Geminin associates with and promotes histone acetylation at neurodevelopmental genes, while Geminin and Zic1 bind a shared gene subset. Geminin- and Zic1-associated genes exhibit embryonic nervous system-enriched expression and encode other regulators of neural development. Both Geminin and Zic1-associated peaks are enriched for Zic1 consensus binding motifs, while Zic1-bound peaks are also enriched for Sox3 motifs, suggesting co-regulatory potential. Accordingly, we found that Geminin and Zic1 could cooperatively activate the expression of several shared targets encoding transcription factors that control neurogenesis, neural plate patterning, and neuronal differentiation. We used these data to construct gene regulatory networks underlying neural fate acquisition. Establishment of this molecular program in nascent neuroectoderm directly links early neural cell fate acquisition with regulatory control of later neurodevelopment.

No MeSH data available.