Epigenomic mechanisms controlling beta cell development and regeneration

TRABA, S.A.; CANDY H.-H. CHO; PECCI, A.; MAESTRO, M.A.; VALLIER, L.; CHHATRIWALA, M.; FERRER, J.; RODRÍGUEZ SEGUÍ, S.A.

Buenos Aires

Encuentro; Pancreas 2017; 2017

International Association of Pancreatology (IAP)

p { margin-bottom: 0.1in; direction: ltr; color: rgb(0, 0, 10); line-height: 120%; text-align: left; }p.western { font-family: "Cambria", serif; font-size: 12pt; }p.cjk { font-family: "ＭＳ 明朝"; font-size: 12pt; }p.ctl { font-size: 12pt; }a:link { color: rgb(0, 0, 255); }Thegenomic regulatory programs that underlie human organogenesis arepoorly understood. Human pancreas development, in particular, haspivotal implications for pancreatic regeneration, cancer, anddiabetes. We have nowcreated maps of transcripts,active enhancers, andtranscription factor networks inpancreatic multipotent progenitors obtained from human embryos, orderived invitro fromhuman embryonic stem cells. This revealed that artificial progenitorsrecapitulate salient transcriptional and epigenomic features of theirnatural counterparts. Using this resource, we show that TEAD1, atranscription factor associated with Hippo signaling, is a corecomponent of the active cis-regulatory modules in pancreaticprogenitors. TEAD1-bound enhancers thus provide a selective genomicregulatory network for activation of genes encoding regulators ofsignaling pathways and stage-specific transcription factors that areessential for normal pancreas development. Accordingly, chemical andgenetic perturbations of TEAD and its co-activator YAP inhibitedexpression of known regulators such as FGFR2and SOX9,andsuppressed the proliferation and expansion of mouse and zebrafishpancreatic progenitors. These findings provide a resource of activeenhancers and transcripts in human pancreatic multipotentprogenitors, and uncover a central role of TEAD and YAP assignal-responsive regulators of the transcriptional program of earlypancreas development.Inthis talk I will make an overview of epigenetic research and how thismight help to understand the developmental programs in humanorganogenesis, with special emphasis on our lastest results showinghow other signaling pathways might interfere with the gene expressionregulation controlled by TEAD and YAP during pancreas development. Aswell, from a nanobioengineering point of view, I will discuss howmicrofluidic devices might improve pancreatic epigenetic research byaccurately sorting pancreatic cell populations and pancreatic islets.