Identification of Highly Conserved Putative Developmental Enhancers Bound by SOX3 in Neural Progenitors Using ChIP-Seq

Abstract

The transcription factor SOX3 is expressed within most neural progenitor (NP) cells of the vertebrate central nervous system (CNS) and is essential for normal brain development in mice and humans. However, despite the widespread expression of Sox3, CNS defects in null mice are relatively mild due to functional redundancy with the other SOXB1 sub-group members Sox1 and Sox2. To further understand the molecular function of SOX3, we investigated the genome-wide binding profile of endogenous SOX3 in NP cells using ChIP-seq. SOX3 binding was identified at over 8,000 sites, most of which were intronic or intergeneic and were significantly associated with neurodevelopmental genes. The majority of binding sites were moderately or highly conserved (phastCons scores >0.1 and 0.5, respectively) and included the previously characterised, SOXB1-binding Nestin NP cell enhancer. Comparison of SOX3 and published ChIP-Seq data for the co-activator P300 in embryonic brain identified hundreds of highly conserved putative enhancer elements. In addition, we identified a subset of highly conserved putative enhancers for CNS development genes common to SOXB1 members in NP cells, all of which contained the SOX consensus motif (ACAAWR). Together these data implicate SOX3 in the direct regulation of hundreds of NP genes and provide molecular insight into the overlapping roles of SOXB1 proteins in CNS development.

SOX9 modulates the expression of key transcription factors required for heart valve development

“…Approximately 22% and 31% of SOX9 peaks in the limb and AVC, respectively, were located either directly over a TSS or in the 5 kb proximal promoter regions. This is in contrast to the SOX9 family members SOX6, which had only 13.5% of bound sites in TSS and 20 kb upstream regions , and SOX3, which had 11% of its bound sites in proximal promoter regions (McAninch and Thomas, 2014). Moreover, a remarkable 63.6% of SOX9 peaks shared between AVC and limb (497 out of 782) were located in the TSS/5 kb promoter regions (Fig.…”

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

“…In Xenopus early embryos, Zic1, Sox3, and Gmnn can regulate each other’s expression and all three activities contribute to establishing neural competence, neural fate acquisition, and maintaining the neural progenitor state. Our ChIP-seq data and that of others3536 suggests that similar regulatory relationships may operate during mammalian neural fate acquisition, with Gmnn regulating Sox3 acetylation, while both Sox3 and Gmnn associate with the Zic1 gene during neural fate acquisition (Fig. 7E).…”

“…( 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.…”

The Cadherin Superfamily in Neural Circuit Assembly

“…As was found for N-cadherin, each of the non-clustered δ-pcdhs is a target of the SoxB1 proteins, Sox2 and Sox3, suggesting that they are expressed in neural progenitors (Bergsland et al 2011; McAninch and Thomas 2014). Similarly, in zebrafish, pcdh18a and pcdh18b were shown to be direct targets of SoxB1 proteins (Okuda et al 2010).…”