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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.


Gmnn-associated genes and genes that undergo Gmnn-dependent histone acetylation exhibit embryonic CNS-enriched expression and neurodevelopmental function.(A) Overlap between Gmnn-bound peaks and associated genes in ES cells and in NE. (B–E) Gene expression levels in ES cells and in embryonic and adult CNS were (B,C) defined for all Gmnn-associated genes and expressed as a z-score or (D,E) defined for Gmnn-associated transcription factors and subjected to hierarchical clustering. (F,G) GO term enrichment for Gmnn-associated genes (in ES and in NE). Subset shown here had at least two-fold enriched expression in the E14 CNS versus ES cells. Additional GO analysis is in Supplementary Fig. S5. (H) Genes that exhibit Gmnn-dependent histone acetylation are compared to those bound by Gmnn in NE, and (I) GO analysis of the subset of genes with Gmnn-dependent acetylation that has E14 CNS-enriched expression was defined as in (F,G). p-value for A, H (Chi-square test with Yates’ correction) <2.2 × 10−16.
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f3: Gmnn-associated genes and genes that undergo Gmnn-dependent histone acetylation exhibit embryonic CNS-enriched expression and neurodevelopmental function.(A) Overlap between Gmnn-bound peaks and associated genes in ES cells and in NE. (B–E) Gene expression levels in ES cells and in embryonic and adult CNS were (B,C) defined for all Gmnn-associated genes and expressed as a z-score or (D,E) defined for Gmnn-associated transcription factors and subjected to hierarchical clustering. (F,G) GO term enrichment for Gmnn-associated genes (in ES and in NE). Subset shown here had at least two-fold enriched expression in the E14 CNS versus ES cells. Additional GO analysis is in Supplementary Fig. S5. (H) Genes that exhibit Gmnn-dependent histone acetylation are compared to those bound by Gmnn in NE, and (I) GO analysis of the subset of genes with Gmnn-dependent acetylation that has E14 CNS-enriched expression was defined as in (F,G). p-value for A, H (Chi-square test with Yates’ correction) <2.2 × 10−16.

Mentions: Genome-wide profiles of Geminin-associated chromatin were defined for both undifferentiated ES cells and after three days of neuroectodermal cell fate acquisition in vitro, as described above. Bound peaks were mapped to the nearest transcription start sites to define gene sets associated with Gmnn in ES and NE. Interestingly, one quarter (247; 26.1%) of the Gmnn associated genes in ES cells were still associated with Gmnn in NE (Fig. 3A). Of these genes, 90 had consistent Gmnn peak locations both in ES cells and during NE fate acquisition, while at the other genes Gmnn associated with a different peak within or near the same gene in ES versus NE (Fig. 3A).


Gene regulatory networks in neural cell fate acquisition from genome-wide chromatin association of Geminin and Zic1
Gmnn-associated genes and genes that undergo Gmnn-dependent histone acetylation exhibit embryonic CNS-enriched expression and neurodevelopmental function.(A) Overlap between Gmnn-bound peaks and associated genes in ES cells and in NE. (B–E) Gene expression levels in ES cells and in embryonic and adult CNS were (B,C) defined for all Gmnn-associated genes and expressed as a z-score or (D,E) defined for Gmnn-associated transcription factors and subjected to hierarchical clustering. (F,G) GO term enrichment for Gmnn-associated genes (in ES and in NE). Subset shown here had at least two-fold enriched expression in the E14 CNS versus ES cells. Additional GO analysis is in Supplementary Fig. S5. (H) Genes that exhibit Gmnn-dependent histone acetylation are compared to those bound by Gmnn in NE, and (I) GO analysis of the subset of genes with Gmnn-dependent acetylation that has E14 CNS-enriched expression was defined as in (F,G). p-value for A, H (Chi-square test with Yates’ correction) <2.2 × 10−16.
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Related In: Results  -  Collection

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f3: Gmnn-associated genes and genes that undergo Gmnn-dependent histone acetylation exhibit embryonic CNS-enriched expression and neurodevelopmental function.(A) Overlap between Gmnn-bound peaks and associated genes in ES cells and in NE. (B–E) Gene expression levels in ES cells and in embryonic and adult CNS were (B,C) defined for all Gmnn-associated genes and expressed as a z-score or (D,E) defined for Gmnn-associated transcription factors and subjected to hierarchical clustering. (F,G) GO term enrichment for Gmnn-associated genes (in ES and in NE). Subset shown here had at least two-fold enriched expression in the E14 CNS versus ES cells. Additional GO analysis is in Supplementary Fig. S5. (H) Genes that exhibit Gmnn-dependent histone acetylation are compared to those bound by Gmnn in NE, and (I) GO analysis of the subset of genes with Gmnn-dependent acetylation that has E14 CNS-enriched expression was defined as in (F,G). p-value for A, H (Chi-square test with Yates’ correction) <2.2 × 10−16.
Mentions: Genome-wide profiles of Geminin-associated chromatin were defined for both undifferentiated ES cells and after three days of neuroectodermal cell fate acquisition in vitro, as described above. Bound peaks were mapped to the nearest transcription start sites to define gene sets associated with Gmnn in ES and NE. Interestingly, one quarter (247; 26.1%) of the Gmnn associated genes in ES cells were still associated with Gmnn in NE (Fig. 3A). Of these genes, 90 had consistent Gmnn peak locations both in ES cells and during NE fate acquisition, while at the other genes Gmnn associated with a different peak within or near the same gene in ES versus NE (Fig. 3A).

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.