How do enhancers control the expression of the same transcriptional factor in different regions of the nervous system?

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Non-coding DNA regulatory elements or enhancers control tissue and region-specific expression of critical developmental regulators thus playing a crucial role in the correct formation of the embryonic body. However, not much is known how regionalized gene expression is achieved through enhancer action. The proposed PhD project aims to address this issue using the development of the nervous system as a paradigm. During embryogenesis, the brain and the spinal cord are derived from different progenitors and this process is controlled to a large extent by the transcription factor Sox2. Sox2 expression into these two components of the nervous system is directed by two distinct enhancers, N1 in the spinal cord and N2 in the brain. This PhD project will employ brain and spinal cord progenitors derived from human pluripotent stem cells (hPSCs) in order to dissect the function of these two enhancers. Using hPSC differentiation in combination with a variety of techniques including ChiP-seq and CRISPR/Cas9 approaches we aim to:1) define the molecular hallmarks that may distinguish the N1 and N2 enhancers2) examine the differential binding of candidate transcription factors on these enhancers3) identify critical sequence parameters influencing their function.