Decoding cis regulatory control of gene silencing during development

During development cells choose between alternative cell fates, each characterised by specific gene expression. Cis-regulatory elements (CREs) are responsible for directing cell-type-specific gene expression with spatial and temporal precision. Our understanding of CRE function remains limited. Most studies have focused on activating transcription factors (TFs). However, many crucial TFs are repressors, which also have essential roles dictating fate decisions. The mechanisms by which repressors regulate cell-type-specific gene expression during development are not well understood. In contrast to models where inaccessible chromatin enforces silencing, I have identified a chromatin regulatory strategy where CREs acting as silencers remain accessible across alternative cell fates, in mouse neural progenitors. These CREs would act as cell-type-specific enhancers and silencers, switching function without chromatin remodelling, with potential implications for cell plasticity. To understand the molecular regulation of silencer elements, and their developmental phenotype, we will (1) identify the cis-regulatory logic of these CREs, (2) the cell-type specific protein composition of CREs and their silencing mechanisms and (3) how the dynamics of TFs control CRE function. The regulatory principles uncovered here will bridge primary DNA sequence to cell fate choice, with broad applicability across developmental systems and for regenerative medicine.