TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors

CEBOLA, I.; RODRÍGUEZ SEGUÍ, S.A.; 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.; MORÁN, I.; CASTRO, N.; HANLEY, N.A.; GOMEZ-SKARMETA, J.L.; VALLIER, L.; FERRER, J.

NATURE CELL BIOLOGY.

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2015 vol. 17 p. 615 - 626

1465-7392

p { margin-bottom: 0.08in; direction: ltr; color: rgb(0, 0, 10); line-height: 0.07in; text-align: justify; widows: 2; orphans: 2; }p.western { font-family: "Calibri",serif; }p.cjk { font-family: "Times New Roman"; }p.ctl { font-family: "Times New Roman"; }a:link { color: rgb(0, 0, 255); } 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 now 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. 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 controlled by Hippo signaling, is a core component of the combinatorial code of pancreatic progenitor enhancers. TEAD thus activates 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 coactivator 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.