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Neural cell fate acquisition is mediated by transcription factors expressed in nascent neuroectoderm, including Geminin and members of the Zic transcription factor family. In our prior work, we identified chromatin association profiles for Geminin and Zic1 during neural fate acquisition at a genome-wide level (Sankar et al., 2016). We determined how Geminin deficiency affected histone acetylation at gene promoters during this process. We integrated these data to determine 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 cell fate acquisition. Establishment of this molecular program in nascent neuroectoderm directly links early neural cell fate acquisition with regulatory control of later neurodevelopment.
We are characterizing how disruption of this network contributes to the etiology of neural tube defects (NTDs) and other neurodevelopmental disorders. Although NTDs are the second most common birth defect (~1:1000 fetuses and newborns), their causation is poorly understood. This is, in part, because NTD occurrence usually has a multi-factorial etiology, with both genetic and environmental susceptibility factors contributing to phenotypic manifestation and severity. Therefore, defining aspects of this regulatory network that are dysregulated to contribute to NTDs in multiple models may identify core processes that, when disrupted, increase NTD susceptibility. This work also defined novel epigenetic regulators with likely roles in neural development, some of which we are functionally assessing in ongoing work.
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Genome-wide binding profiles for Geminin and Zic1 were used to define gene regulatory networks in neural cell fate acquisition. (A-D) Comparison of Gmnn-associated and Zic1-associated genes in NE. (A) A subset of genes is associated with both Gmnn and Zic1. p-value (Chi-square test with Yates’ correction) < 2.2X10-16. (B) z-scores for enrichment of expression in ES versus CNS tissues for all Zic and/or Gmnn associated genes. (C) Comparison of all Gmnn or Zic1 associated genes, subsets that undergo Gmnn-dependent acetylation, and transcription factors, with their relative enrichment of expression in embryonic CNS tissues. (D) GO enrichment analysis for associated genes with increased versus decreased expression in embryonic CNS, relative to ES cells. (E) Gene regulatory networks in neural cell fate acquisition. Gmnn- and Zic1-associated genes in NE that encode transcription factors and epigenetic regulatory activities were assessed for co-association with Sox2 and Sox3 in ES-derived NE (see text). The set of these genes that exhibit CNS-enriched expression (>two-fold greater expression in E14 CNS, relative to ES cells), and were associated with Gmnn and/or Zic1 plus Sox2 and/or Sox3 were used to build gene regulatory networks showing associations.