Professor of Developmental Biology
From stem cells to tissues: Notch regulatory networks in development
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. Elucidating how Notch signalling functions in different contexts is thus not only vital for understanding development but also has the potential to identify novel markers to aid treatments for human diseases.
Despite the relative simplicity of its transduction pathway, the consequences of activating Notch differ significantly according to the cell context. This is powerfully illustrated by the diverse developmental outcomes specified by Notch (e.g. stem cell maintenance, progenitor selection, growth organising boundaries) and by the fact that Notch promotes tumour growth in some circumstances but prevents it in others. Although we are aware of these different consequences, we know little of how they come about. For example, can Notch exert its effects by acting on a small number of genes, that in turn feed forward to regulate many others, or does it, in the extreme case, regulate a large number that are all needed to change cell behaviours? How similar are the sets of genes turned on by Notch in different contexts? These are some of the questions we are addressing through our genome-wide studies of Notch target genes.
We primarily use Drosophila as our model, due to the powerful genetics that allow us to directly test the in vivo importance of novel components and targets. Furthermore, its small genome size facilitates our genome-wide investigations into Notch targets. The extent of conservation with humans (~80% of human disease genes have orthologues in Drosophila) has been emphasised by our identification of genes clearly relevant to human cancers amongst the Notch targets from our Drosophila studies.
Our first genome-wide experiments focussed on muscle progenitors where we have found 125 targets involved in the maintenance of adult myogenic precursors, including many novel genes whose function we are characterizing. We are now decoding our results from a second cell type, related to blood cells, where we find some overlapping and some novel targets. In both cases we find many examples of “incoherent feed-forward loops”, where Notch stimulates the expression both a gene and the repressor of that gene. This may result in a transient window of competence following Notch activation, and has made us interested in the temporal profile of the response.
Current projects focus on:
- the developmental functions of novel targets indentified in our genome-wide screens
- following through cohorts of genes, to understand how Notch regulates specific processes (e.g. progenitor maintenance)
- further genome wide-studies to elucidate the response in different cell types and how the response changes with time
- finding out the genetic and epigenetic mechanisms responsible for conferring different responses.
Current lab members and collaborators
Hadi Boukhatmi (Postdoctoral fellow; EMBO LTF)
Gustavo Cerda-Moya (Postdoctoral fellow)
Maria Gomez-Lamarca (Postdoctoral fellow)
Robert Stojnic (Postdoctoral fellow)
Eva Zacharioudaki (Postdoctoral fellow)
Stephan Chan (PhD student, Croucher Foundation)
Silvie Fexova (PhD student, BBSRC and Cambridge Trusts)
Matthew Jones (PhD student, Wellcome Trust)
Stella Lempidaki (PhD student)
Zoe Pillidge (PhD student, BBSRC)
Agnes Asselin (Lab Technician)
Kat Millen (Lab Manager)
Sara Morais Da Silva (Wellcome Trust Fellow)
Gomez-Lamarca MJ, Snowdon LA, Seib E, Klein T, Bray SJ, (2015), Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling, Journal of Cell Biology, 210(2):303-18
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 Journal, 34(14):1889-904.
Torella R, LiJ, Kinrade E, Cerda-Moya G, Contreras AN, Foy R, Stojnic R, GlenRC, Kovall RA, Adryan B, Bray SJ, (2014), A combination of computational and experimental approaches identifies DNA sequence constraints associated with target site binding specificity by the transcription factor CSL, Nucleic Acids Research, 42(16):10550-63
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
EndoK, KarimMR, TaniguchiH, Krejci K, Kinameri E, SiebertM, ItoK, Bray SJ, Moore AW, (2011), Olfactory receptor neuron identity is diversified by the Drosophila Evi1/Prdm16 Homologue Hamlet that mediates chromatin modification at Notch-target loci, Nature Neuroscience, 15(2): 224-33
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
Glittenberg M, Pitsouli C, Garvey C, Delidakis C, Bray SJ, (2006), Role of conserved intracellular motifs in Serrate signalling, cis-inhibition and endocytosis, EMBO Journal, 25: 4697-706
Bray SJ, (2006), Notch Signalling: a simple pathway becomes complex, Nature Reviews in Molecular Cell Biology, 7: 678-89
Bray SJ, Musisi H, Bienz M, (2005), Bre1 is required for Notch signalling and histone modification, Developmental Cell, 8: 279-86