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Browsing MN - Artigos by Author "Castro, Diogo S."
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- Ascl1 Coordinately Regulates Gene Expression and the Chromatin Landscape during NeurogenesisPublication . Raposo, Alexandre A.S.F.; Vasconcelos, Francisca F.; Drechsel, Daniela; Marie, Corentine; Johnston, Caroline; Dolle, Dirk; Bithell, Angela; Gillotin, Sébastien; van den Berg, Debbie L.C.; Ettwiller, Laurence; Flicek, Paul; Crawford, Gregory E.; Parras, Carlos M.; Berninger, Benedikt; Buckley, Noel J.; Guillemot, François; Castro, Diogo S.The proneural transcription factor Ascl1 coordinates gene expression in both proliferating and differentiating progenitors along the neuronal lineage. Here, we used a cellular model of neurogenesis to investigate how Ascl1 interacts with the chromatin landscape to regulate gene expression when promoting neuronal differentiation. We find that Ascl1 binding occurs mostly at distal enhancers and is associated with activation of gene transcription. Surprisingly, the accessibility of Ascl1 to its binding sites in neural stem/progenitor cells remains largely unchanged throughout their differentiation, as Ascl1 targets regions of both readily accessible and closed chromatin in proliferating cells. Moreover, binding of Ascl1 often precedes an increase in chromatin accessibility and the appearance of new regions of open chromatin, associated with de novo gene expression during differentiation. Our results reveal a function of Ascl1 in promoting chromatin accessibility during neurogenesis, linking the chromatin landscape at Ascl1 target regions with the temporal progression of its transcriptional program.
- MyT1 Counteracts the Neural Progenitor Program to Promote Vertebrate NeurogenesisPublication . Vasconcelos, Francisca F.; Sessa, Alessandro; Laranjeira, Cátia; Raposo, Alexandre A.S.F.; Teixeira, Vera; Hagey, Daniel W.; Tomaz, Diogo M.; Muhr, Jonas; Broccoli, Vania; Castro, Diogo S.The generation of neurons from neural stem cells requires large-scale changes in gene expression that are controlled to a large extent by proneural transcription factors, such as Ascl1. While recent studies have characterized the differentiation genes activated by proneural factors, less is known on the mechanisms that suppress progenitor cell identity. Here, we show that Ascl1 induces the transcription factor MyT1 while promoting neuronal differentiation. We combined functional studies of MyT1 during neurogenesis with the characterization of its transcriptional program. MyT1 binding is associated with repression of gene transcription in neural progenitor cells. It promotes neuronal differentiation by counteracting the inhibitory activity of Notch signaling at multiple levels, targeting the Notch1 receptor and many of its downstream targets. These include regulators of the neural progenitor program, such as Hes1, Sox2, Id3, and Olig1. Thus, Ascl1 suppresses Notch signaling cell-autonomously via MyT1, coupling neuronal differentiation with repression of the progenitor fate.