The Role of Cdx in Mesoderm Cell Fate Specification

Abstract

Roles for the Cdx transcription factors during anteroposterior patterning and development of the posterior embryo have been well described, yet little is known about Cdx functions during mesoderm specification. In the studies presented here, novel roles for Cdx during gastrulation are presented. In the first of two studies, the role of Cdx factors during cardiac mesoderm specification is investigated. We demonstrate that Cdx factors epigenetically restrict cardiac progenitor specification, preventing the ectopic expression of cardiogenic genes within progenitor mesodermal populations. We provide evidence to suggest that this occurs through interaction with Brg1, a subunit of the SWI/SNF chromatin remodeling complex, and propose a molecular mechanism by which Cdx-mediated recruitment of the SWI/SNF complex is required to maintain repression of cardiac targets at developmental stages where Cdx transcription factors are no longer expressed. Following this, Cdx-dependent gene expression programs were identified in the extra-embryonic yolk sac. RNA-sequencing of Cdx-mutant yolk sacs revealed novel Cdx-dependent gene targets involved in ion and nutrient transport, functions analogous to those previously described for Cdx in the adult intestinal epithelium. Subsequent experimentation revealed that, for a subset of these targets, regulation correlates with the maintenance of H3K27me3 marks. Finally, we provide evidence to suggest Cdx-dependent H3K27me3 marks are established at early developmental stages, when yolk sac progenitors are specified from the streak. Together, these studies describe novel roles for Cdx factors in mesoderm specification during gastrulation, and evoke molecular mechanisms by which Cdx might program early mesodermal populations for gene expression at later developmental stages through interactions with epigenetic regulatory complexes.