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ST18 represents a novel transcriptional repressor ensuring proper expression kinetics during early cortical development

ABSTRACT: Cortical development is a tightly spatiotemporally regulated process in which cell-fate specification is accompanied by stable resetting of transcriptional programs. However, the full repertoire of transcriptional regulators orchestrating such transcriptome changes remains largely incomprehensive. Applying a bioinformatics predictive approach we aimed to identify novel transcription factors contriuting to transcriptional reprogramming during embryonic neurogenesis and identified the neuronal tissue specific transcription factor St18 to be essential for neurogenesis in vitro and in vivo. We find that embryonic stem cells deficient for St18 are not able to efficiently differentiate along neuronal lineage and St18 depleted cells in the developing cortex do not elongate in shape and reside in the VZ/SVZ region but display premature expression of the upper layer neuronal marker Satb2. Relation of St18 binding to genes deregulated upon St18 depletion in vivo revealed St18 to function as transcriptional repressor at the time when neurogenesis is initiated. St18 ensures efficient onset of cortical neurogenesis by inhibiting expression of the self-renewal maintaining factor Hes1 that represses differentiation genes in neuronal progenitors as well as downregulation of genes that are essential for differentiation into mesodermal and endodermal lineage such as Lama5, Traf4 and Tab1. Furthermore we find this transcriptional repressor to be bound to genes that are important for later stages of neurogenesis when the neuronal circuitry is established likely to keep them in repressed state in the time window of neurogenesis when they are not yet required. These genes important for axon guidance and neurite outgrowth are subsequently prematurely upregulated in St18 depleted cortical cells. We further observe St18 to be bound to a significant fraction of intergenic enhancers where it regulates expression of nearest genes that Our data establish St18 as a novel transcriptional regulator during early onset of cortical neurogenesis that is essential to ensure timely expression kinetics of phase and lineage specific genes.

ORGANISM(S): Mus musculus

PROVIDER: GSE66436 | GEO | 2021/02/01

REPOSITORIES: GEO

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Project description:Transcriptional targets of neurogenin (Ngnr1) were identified by over-expression of an inducible form of neurogenin in Xenopus ectodermal explants. The effects of co-expressing the nucleoprotein geminin on Ngnr1-dependent target gene transactivation were defined. Regulating the transition from lineage-restricted progenitors to terminally differentiated cells is a central aspect of nervous system development. Here, we investigated the role of the nucleoprotein geminin in regulating neurogenesis at a mechanistic level during both Xenopus primary neurogenesis and mammalian neuronal differentiation in vitro. The latter work utilized both neural cells derived from embryonic stem and embryonal carcinoma cells in vitro and neural stem cells from mouse forebrain. In all of these contexts, geminin antagonized the ability of neural bHLH transcription factors to activate transcriptional programs promoting neurogenesis. Furthermore, geminin promoted a bivalent chromatin state, characterized by the presence of both activating and repressive histone modifications, at genes encoding transcription factors that promote neurogenesis. This epigenetic state restrains the expression of genes that regulate commitment of undifferentiated stem and neuronal precursor cells to neuronal lineages. Geminin is highly expressed in undifferentiated neuronal precursor cells but is downregulated prior to differentiation. Therefore, these data support a model whereby geminin promotes the neuronal precursor cell state by modulating both the epigenetic status and expression of genes encoding neurogenesis-promoting factors. Additional developmental signals acting in these cells can then control their transition toward terminal neuronal or glial differentiation during mammalian neurogenesis. A dexamethasone-inducible (GR ligand binding domain fused) form of Xenopus neurogenin-related 1, NgnrGR, was over-expressed in Xenopus embryonic ectodermal explants, in the presence or absence of over-expressed geminin. Induction of Ngnr1 activity was used to define direct targets as previously described (EMBO J. 26(24): 5093-5108). The ability of geminin to suppress Ngnr1-dependent transactivation of its target gene programs was determined.

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ST18 represents a novel transcriptional repressor ensuring proper expression kinetics during early cortical development

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