Professor Sarah Bray

From stem cells to tissues: Notch regulatory dynamics in development and disease

To make and organize different tissues, cells must decipher information from developmental signalling pathways. Currently we know little about how the information is encoded and decoded, to generate the right balance and arrangements of cell types. Cells face the challenge of transmitting this information accurately, so that cell-surface signals are translated into correct transcriptional responses. How this is achieved mechanistically remains a major question.

The Notch pathway is one of a small handful of cell signalling pathways that coordinate animal development, regulating the types and numbers of cells formed in many developmental contexts. Its roles include the maintenance of stem cell/progenitor populations, a requirement that continues during tissue homeostasis in the adult. Aberrant Notch function is also implicated in many diseases including dementia and many cancers.  Discovering how the appropriate responses to Notch are configured is therefore vital for deciphering when combinations of genetic abnormalities are likely to be oncogenic, and for informing strategies for targeted therapies.

In our research we use a combination of live-imaging, genetic, biochemical and genomic approaches in Drosophila and in human cells to discover the fundamental mechanisms that reset and sculpt transcriptional responses to Notch. These mechanisms are essential to bring about different outcomes and to avoid inappropriate gene expression programmes being turned on.

We are currently investigating the following questions:

How are Notch signals decoded by enhancers in real time in vivo? To address this, we are using the MS2/MCP system to visualize foci of nascent transcripts in vivo. The measurements give us a real-time, quantitative, read-out of signalling responses from individual genes on a cell-by-cell basis within the embryo. We will use this information to determine the dynamics of signalling during developmental decisions and to understand how this is received and translated by the responding enhancers.

What epigenetic mechanisms reset transcriptional responses to Notch during cell state transitions? We are investigating the role of chromatin remodelling complexes in resetting enhancers at different steps within a stem cell lineage, using live-imaging, genomic and genetic approaches to discover how they are deployed in the context of Notch signalling. Answering this question is important for deciphering how different outcomes from Notch activation are programmed and has implications for how mutations lead to cancer in some contexts but not others.

How do Notch regulated enhancers select and communicate with promoters? We are using genomic profiling methods and molecular assays to measure changes in enhancer-promoter interactions in response to signalling and to identify factors that are important for the correct coupling to occur.

What roles tissue geometry and forces play in shaping signalling dynamics? Notch ligands are transmembrane proteins. The extent of cell interfaces, strength of cell junctions and/or forces applied across the tissue could all therefore affect the levels and duration of signalling. By live-imaging Notch responses in different contexts, in conjunction with methods to analyze tissue mechanics, we will learn how tissue organization impacts on signalling dynamics

Main sources of funding: Medical Research Council, Wellcome Trust, BBSRC

Current lab members and collaborators

Hadi Boukhatmi (Postdoctoral fellow; EMBO LTF),

Maria Gomez-Lamarca (Postdoctoral fellow)

Torcato Martins (Postdoctoral fellow)

Julia Falo SanJuan (Postdoctoral fellow),

Jonathan Townson (PhD student BBSRC)

Clare Rutland (Lab Technician),

Kat Millen (Lab Manager)

Sara Morais Da Silva (Independent Wellcome Trust Fellow)