IFIBYNE   05513
INSTITUTO DE FISIOLOGIA, BIOLOGIA MOLECULAR Y NEUROCIENCIAS
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors
Autor/es:
RODRÍGUEZ SEGUÍ, S.A.; CEBOLA, I.; CHO, C.H.-H.; BESSA, J.; ROVIRA, M.; LUENGO, M.; CHHATRIWALA, M.; BERRY, A.; PONSA-COBAS, J.; MAESTRO, M.A.; JENNINGS, R.E.; PASQUALI, L.; MORAN, I.; CASTRO, N.; HANLEY, N.A.; GOMEZ SKARMETA, J.L.; VALLIER, L.; FERRER, J.
Lugar:
Jerusalem
Reunión:
Congreso; Joint Meeting of The Islet Study Group and Beta Cell Workshop; 2015
Institución organizadora:
The Islet Study Group
Resumen:
The genomic regulatory programs that underlie human organogenesis are poorly understood. Human pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer, and diabetes. We have created maps of transcripts, active enhancers, and transcription factor networks in pancreatic multipotent progenitors obtained from human embryos, or derived in vitro from human embryonic stem cells (hESCs). This revealed that artificial progenitors recapitulate salient transcriptional and epigenomic features of their natural counterparts. Using this resource, we show that TEAD1, a transcription factor associated with Hippo signaling, is a core component of the active cis-regulatory modules in pancreatic progenitors. Hippo signaling has been previously associated with liver and heart growth, and recent reports have also showed that pancreas-specific disruption of the upstream Hippo kinases Mst1/2 leads to increased proliferation of adult acinar pancreatic cells, which acquire a duct-like morphology and exhibit increased nuclear localization of the pathway co-activator Yap. Here, we show that TEAD1-bound enhancers provide a selective genomic regulatory network for activation of genes encoding regulators of signaling pathways and stage-specific transcription factors that are essential for normal pancreas development. Accordingly, chemical and genetic perturbations of TEAD and its co-activator YAP inhibited expression of known regulators such as FGFR2 and SOX9, and suppressed the proliferation and expansion of mouse and zebrafish pancreatic progenitors. These findings provide a resource of active enhancers and transcripts in human pancreatic multipotent progenitors, and uncover a central role of TEAD and YAP as signal-responsive regulators of the transcriptional program of early pancreas development.