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Professor Sarah Bray PhD

Professor Sarah Bray, PhD

Professor of Developmental Biology

Joint Head of Department

Wellcome Trust Investigator


Office Phone: +44 (0) 1223 765222, Fax: +44 (0) 1223 333786

Research Interests

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)

 

Key Publications

Falo-Sanjuan J, Lammers NC, Garcia HG, Bray SJ. (2019) Enhancer Priming Enables Fast and Sustained Transcriptional Responses to Notch Signaling. Developmental Cell 50(4):411-425.e8

Zacharioudaki E, Falo Sanjuan J, Bray SJ (2019) Mi-2/NuRD complex protects stem cell progeny from mitogenic Notch signaling. Elife;8. pii: e41637.

Pillidge Z, Bray SJ. (2019) SWI/SNF chromatin remodelling controls Notch-responsive enhancer accessibility. EMBO Rep. 2019 Mar 26. pii: e46944.

Boukhatmi H, Bray SJ (2018) A population of adult satellite-like cells in Drosophila is maintained through a switch in RNA-isoforms. Elife. 2018 Apr 9;7. pii: e35954.

Gomez-LamarcaMJ, Falo-Sanjuan. J, StojnicR, Abdul RehmanS, MuresanL, JonesMJ Pillidge Z, Cerda-MoyaG YuanZ BaloulS Valenti P, BystrickyK,  PayreF, O’HolleranK, KovallR, BraySJ (2018) Activation of the Notch signalling pathway in vivo elicits changes in CSL nuclear dynamics, Developmental Cell 44(5):611-623.e7

Bray SJ, Gomez-Lamarca M. (2017) Notch after cleavage. Curr Opin Cell Biol. 51:103-109.

Chan SKK, Cerda-Moya G, Stojnic R, Millen K, Fischer B, Fexova S, Skalska L, Gomez-Lamarca M, Pillidge Z, Russell S, Bray SJ. (2017) Role of co-repressor genomic landscapes in shaping the Notch response. PLoS Genetics 13(11): e1007096.

Bray SJ (2016) Notch Signalling in Context. Nature Reviews in Molecular Cell Biology 17 (11), pp. 722-735

Zacharioudaki E, Housden BE, Garinis G, Stojnic R, Delidakis C, Bray SJ (2016) Genes implicated in stem-cell identity and temporal-program are directly targeted by Notch in neuroblast tumours. Development 143 (2): 219-231

Skalska L, Stojnic R, Li J, Fischer B, Cerda-Moya G, Sakai H, Tajbakhsh S, Russell S, Adryan B, Bray SJ (2015) Chromatin signatures at Notch-regulated enhancers reveal large-scale changes in H3K56ac upon activation. EMBO J 34(14): 1889-1904.

Housden BE, Terriente-Felix A, Bray SJ, (2014), Context dependent enhancers confer alternate modes of Notch regulation on argos, Molecular and Cellular Biology, 34(4):664-7

Terriente-Felix A, Li J, Collins S, Mulligan A, Reekie I, Bernard F, Krejci A, Bray SJ, (2013), Notch co-operates with Lozenge/Runx to lock hemocytes into a differentiation programme, Development, 140(4): 926-37

Djiane A, Krejci A, Bernard F, Fexova S, Millen K, Bray SJ, (2013), Dissecting the mechanisms of Notch induced hyperplasia, EMBO Journal, 32(1): 60-71

Bernard F, Krejci A, Housden B, Adryan B, Bray SJ, (2010), Specificity of Notch pathway activation: Twist controls the transcriptional output in adult muscle progenitors, Development, 137: 2633-42

Bray SJ, Bernard F, (2010), Notch targets and their regulation, Current Topics in Developmental Biology, 92: 253-75

Moshkin YM, Kan TW, Goodfellow H, Bezstarosti K, Maeda RK, Pilyugin M, Karch F, Bray SJ, Demmers JAA, Verrijzer CP, (2009), Histone Chaperones ASF1 and NAP1 Differentially Modulate Removal of Active Histone Marks by LID-RPD3 Complexes during NOTCH Silencing, Molecular Cell, 35: 782-93

Krejci A, Bernard F, Housden BE, Collins S, Bray SJ, (2009), Direct Response to Notch Activation: Signaling Crosstalk and Incoherent Logic, Science Signaling 2: ra1

Goodfellow H, Krejci A, Moshkin Y, Verrijzer CP, Karch F, Bray SJ, (2007), Gene-Specific Targeting of the Histone Chaperone Asf1 to Mediate Silencing, Developmental Cell 13: 593-600

Krejci A, Bray SJ, (2007), Notch activation stimulates transient and selective binding of Su(H)/CSL to target enhancers, Genes and Development, 21: 1322-7

Bray SJ, (2006), Notch Signalling: a simple pathway becomes complex, Nature Reviews in Molecular Cell Biology, 7: 678-89

 

Above: Notch activity in the developing ommatidia of the fly eye. Notch is active (red) in a single cell in each ommatidia where it confers specific photoreceptor fate and helps orient the whole structure (Red indicates cells where Notch is active; green (spalt) marks a subset of photoreceptors and cone cells and blue (coracle) highlights cell membranes marking all cells.) See Cooper, M. and Bray, S.J. (1999) Nature 397, 526-530

Above: Proximal/distal patterning in the leg. Notch activity is important in defining different territories of gene expression involved in growth and patterning of the leg (red, barH1; green, Bric-a-brac; red, dacshund). See de Celis-Ibeas, J. and Bray, S.J. (2003) Development 130, 5943-5942

Above: ChIP peaks (blue) reveal binding of Su(H) across the E(spl) complex (see Krejci et al, 2009). Su(H) is the DNA-binding protein in the Notch pathway. (Black boxes depict genes; red/orange graphs indicate positions with sequence matches to Su(H) binding sites)