Specificity of Notch pathway activation: twist controls the transcriptional output in adult muscle progenitors.
Cell-cell signalling mediated by Notch regulates many different developmental and physiological processes and is involved in a variety of human diseases. Activation of Notch impinges directly on gene expression through the Suppressor of Hairless [Su(H)] DNA-binding protein. A major question that remains to be elucidated is how the same Notch signalling pathway can result in different transcriptional responses depending on the cellular context and environment. Here, we have investigated the factors required to confer this specific response in Drosophila adult myogenic progenitor-related cells. Our analysis identifies Twist (Twi) as a crucial co-operating factor. Enhancers from several direct Notch targets require a combination of Twi and Notch activities for expression in vivo; neither alone is sufficient. Twi is bound at target enhancers prior to Notch activation and enhances Su(H) binding to these regulatory regions. To determine the breadth of the combinatorial regulation we mapped Twi occupancy genome-wide in DmD8 myogenic progenitor-related cells by chromatin immunoprecipitation. Comparing the sites bound by Su(H) and by Twi in these cells revealed a strong association, identifying a large spectrum of co-regulated genes. We conclude that Twi is an essential Notch co-regulator in myogenic progenitor cells and has the potential to confer specificity on Notch signalling at over 170 genes, showing that a single factor can have a profound effect on the output of the pathway.
Bernard
Fred
F
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
Krejci
Alena
A
Housden
Ben
B
Adryan
Boris
B
Bray
Sarah J
SJ
D000375:Aging; D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D055106:Genome-Wide Association Study; D018482:Muscle, Skeletal / Q000378:metabolism*; D011485:Protein Binding; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
D029721:Drosophila Proteins; C497759:N protein, Drosophila; D051880:Receptors, Notch; D012097:Repressor Proteins; C088731:Su(H) protein, Drosophila; D014157:Transcription Factors; C497753:Twi protein, Drosophila; D051879:Twist-Related Protein 1; C076560:H protein, Drosophila