The Sox2 transcription factor in brain development and disease:
genome-wide studies in neural stem cells

19th June 2015
Versione stampabile

Venue: Edificio Povo 2, via Sommarive nr. 9, Povo (Tn) - Room B102
 at 2:00 p.m.

  • Silvia Nicolis -  Dipartimento di biotecnologie e bioscienze, Università degli Studi di Milano, Milan, Italy

During embryonic development, the orchestrated activity of our genes gives rise to our most complex organ, the brain. Our laboratory works on transcription factor Sox2, an important regulator of the transcriptional regulatory networks leading to brain embryogenesis and postnatal maintenance: by conditional knockout in mouse, we found that Sox2 is essential for developing various specific brain regions, including the hippocampus and the basal ganglia, recapitulating defects seen in patients carrying mutations in human Sox2. Neural stem cells, whose regulated self-renewal and differentiation shape the developing brain, require Sox2 function. By genomic approaches (ChIA-PET, ChIPseq) we are now addressing the function of Sox2 in an aspect of gene regulation that is emerging as fundamental: the 3-D organization of the genome within the nucleus, in particular long-range interactions connecting genes to transcriptional regulatory elements scattered within the genome, at great distance. Sox2 deletion leads to profound changes in chromatin connectivity within brain-derived neural stem cells, leading to loss of
long-range interactions involving sequences that behave as brain-specific enhancers in transgenic assays.Cancer stem cells found in neural tumors can be viewed as a diseased state of normal neural stem cells. We found, by our Sox2flox mouse, that Sox2 is required to maintain cancer stem cells within a glioma mouse model, mirroring its requirement by normal neural stem cells. Unexpectedly, immunotherapy directed against Sox2 epitopes significantly prolonged survival, pointing to Sox2 itself, and its downstream effectors, as novel targets for therapy approaches.