In the previous funding cycle, we examined the mechanism through which FGF and BMP specify the endoderm to adopt a hepatic fate. We revealed that FGF has a critical role in controlling expression of a WNT inhibitor called NKD1. NKD1 transiently suppresses WNT activity, which is needed to promote hepatic fate. BMP controls hepatic fate through activation of SMAD1. This signaling pathway regulates expression of several developmental regulators. Like FGF, BMP induces NKD1. BMP also controls expression of several regulators of chromatin structure including TFAP2A and ARID5B. In the current proposal, we will study the roles of TFAP2A and ARID5B in generating hepatic progenitor cells. We had also had previously shown that GATA6 is necessary for hepatic specification in mouse embryos. We, therefore, propose to determine the mechanism through which GATA6 controls hepatic fate. We hypothesize that GATA6 acts as a pioneer transcription factor to promote the competency of the endoderm to respond to inductive cues.
We will use human induced pluripotent stem cells (iPSCs) as a model to understand the fundamental mechanisms through which the liver is formed. We will determine whether GATA6 acts as a pioneer factor to open chromatin around liver enhancers. We will also determine whether two BMP4 immediate early target genes, TFAP2A and ARID5B, are needed for the formation of liver cells.
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