Browsing by Author "Drechsel, Daniela"
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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.
- Characterization of the neural stem cell gene regulatory network identifies OLIG2 as a multifunctional regulator of self-renewalPublication . Mateo, Juan L; van den Berg, Debbie L C; Haeussler, Maximilian; Drechsel, Daniela; Gaber, Zachary B; Castro, Diogo S; Robson, Paul; Crawford, Gregory E; Flicek, Paul; Ettwiller, Laurence; Wittbrodt, Joachim; Guillemot, François; Martynoga, BenThe gene regulatory network (GRN) that supports neural stem cell (NS cell) self-renewal has so far been poorly characterized. Knowledge of the central transcription factors (TFs), the noncoding gene regulatory regions that they bind to, and the genes whose expression they modulate will be crucial in unlocking the full therapeutic potential of these cells. Here, we use DNase-seq in combination with analysis of histone modifications to identify multiple classes of epigenetically and functionally distinct cis-regulatory elements (CREs). Through motif analysis and ChIP-seq, we identify several of the crucial TF regulators of NS cells. At the core of the network are TFs of the basic helix-loop-helix (bHLH), nuclear factor I (NFI), SOX, and FOX families, with CREs often densely bound by several of these different TFs. We use machine learning to highlight several crucial regulatory features of the network that underpin NS cell self-renewal and multipotency. We validate our predictions by functional analysis of the bHLH TF OLIG2. This TF makes an important contribution to NS cell self-renewal by concurrently activating pro-proliferation genes and preventing the untimely activation of genes promoting neuronal differentiation and stem cell quiescence.