MN - Artigos
Permanent URI for this collection
Browse
Browsing MN - Artigos by Author "Castro, Diogo S"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
- 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.
- Zeb1 controls neuron differentiation and germinal zone exit by a mesenchymal-epithelial-like transitionPublication . Singh, Shalini; Howell, Danielle; Trivedi, Niraj; Kessler, Ketty; Ong, Taren; Rosmaninho, Pedro; Raposo, Alexandre ASF; Robinson, Giles; Roussel, Martine F; Castro, Diogo S; Solecki, David JIn the developing mammalian brain, differentiating neurons mature morphologically via neuronal polarity programs. Despite discovery of polarity pathways acting concurrently with differentiation, it's unclear how neurons traverse complex polarity transitions or how neuronal progenitors delay polarization during development. We report that zinc finger and homeobox transcription factor-1 (Zeb1), a master regulator of epithelial polarity, controls neuronal differentiation by transcriptionally repressing polarity genes in neuronal progenitors. Necessity-sufficiency testing and functional target screening in cerebellar granule neuron progenitors (GNPs) reveal that Zeb1 inhibits polarization and retains progenitors in their germinal zone (GZ). Zeb1 expression is elevated in the Sonic Hedgehog (SHH) medulloblastoma subgroup originating from GNPs with persistent SHH activation. Restored polarity signaling promotes differentiation and rescues GZ exit, suggesting a model for future differentiative therapies. These results reveal unexpected parallels between neuronal differentiation and mesenchymal-to-epithelial transition and suggest that active polarity inhibition contributes to altered GZ exit in pediatric brain cancers.