Transcription factor binding integration and dynamics in developmental cell fate choice

Project ID: 2531ad1546

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UCL Lead department: Laboratory for Molecular Cell Biology (LMCB)

Project Summary:

During development, cells specialise from multipotent to differentiated fates, building our organs. This specialisation requires the control of gene expression programs. Cis-regulatory elements drive gene expression with exquisite spatial and temporal resolution. But beyond serving as transcription factor binding platforms, how these elements act is unclear. A key feature of cis-regulatory elements is that they must integrate binding of both activating and repressive transcription factors. The tools available to date, such as ChIP-seq, have only allowed us to get snapshots of transcription factors binding to the genome. Recent developments in single molecule live cell imaging now allow us to follow individual TF molecules within the nucleus and infer their binding to chromatin. This has revealed that TFs bind chromatin only transiently. Work from our collaborator and pioneer in single molecule live cell imaging, James Liu (Janelia) has also shown that SOX2 forms clusters of high density. The ventral spinal cord is the perfect model to address these questions. We have extensive knowledge on the regulators and cell fates, including pan-activators, cell type specific repressors and bi-functional signaling effectors. But how do these inputs integrate at cis-regulatory elements to drive gene expression or silencing? We will address this by combining cutting-edge genomics methods single molecule live cell imaging during neural differentiation.

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