Gata6 potently initiates reprograming of pluripotent and differentiated cells to extraembryonic endoderm stem cells

Abstract

Transcription factor-mediated reprograming is a powerful method to study cell fate changes. In this study, we demonstrate that the transcription factor Gata6 can initiate reprograming of multiple cell types to induced extraembryonic endoderm stem (iXEN) cells. Intriguingly, Gata6 is sufficient to drive iXEN cells from mouse pluripotent cells and differentiated neural cells. Furthermore, GATA6 induction in human embryonic stem (hES) cells also down-regulates pluripotency gene expression and up-regulates extraembryonic endoderm (ExEn) genes, revealing a conserved function in mediating this cell fate switch. Profiling transcriptional changes following Gata6 induction in mES cells reveals step-wise pluripotency factor disengagement, with initial repression of Nanog and Esrrb, then Sox2, and finally Oct4, alongside step-wise activation of ExEn genes. Chromatin immunoprecipitation and subsequent high-throughput sequencing analysis shows Gata6 enrichment near pluripotency and endoderm genes, suggesting that Gata6 functions as both a direct repressor and activator. Together, this demonstrates that Gata6 is a versatile and potent reprograming factor that can act alone to drive a cell fate switch from diverse cell types.

Esrrb directly binds to Gata6 promoter and regulates its expression with Dax1 and Ncoa3

“…Moreover, Esrrb binds to the Gata6 promoter region. These findings are consistent with previous findings: Esrrb induces Gata6 expression [22,26] and binds to the Gata6 promoter region [30]. Interestingly, Esrrb-deficient embryos had impaired placental formation [33], although co-expression of Esrrb and Sox2 was sufficient for multipotency of trophoblast stem cells [34], further indicating the importance of Esrrb in the development of extraembryonic tissues.…”

“…Gata6, a zinc-finger transcription factor, is important for the development of ExEn, and artificial overexpression of Gata6 in ES or neural stem cells of mice and human ES cells triggers differentiation into ExEn [29,30].…”

Dual functions of silver nanoparticles in F9 teratocarcinoma stem cells, a suitable model for evaluating cytotoxicity- and differentiation-mediated cancer therapy

“…induce rapid reprograming of mESCs to induced embryonic endoderm stem cells. 86 Several members of the Wnt gene family are expressed in very specific patterns in the embryonic mesoderm and have been involved in the regulation of hematopoiesis. 87,88 Wnt5 signaling is critical for regulating normal developmental processes, including stem cell selfrenewal, proliferation, differentiation, migration, adhesion, and polarity.…”

Synthetic Morphogenesis

“…One example application might be to implement an automatic multistep stem cell differentiation protocol without laborious sequential application of chemical inducers (Schiesser et al 2014). For example, a gene circuit could recapitulate the ontogeny of pancreatic b cells by sequentially expressing Gata6, Pdx1, Ngn3, and Pax4 to drive differentiation of stem cells through definitive endoderm (Wamaitha et al 2015), pancreatic endoderm (Kubo et al 2011), and b cells, respectively ( Fig. 1, left) (Collombat et al 2009).…”

“…As the discipline's tools become more powerful, they are beginning to enable the construction of systems that have dynamic behavior and nontrivial emergent properties similar to those of natural morphogenetic processes. Synthetic gene circuits can detect a cell's type (Miki et al 2015), metabolic state (Callura et al 2012), (bio-) chemical signals (Weber et al 2007), and light (Müller et al 2014;Schmidl et al 2014); they can use these inputs, combinatorially or sequentially, to alter the cell's shape (Yeh et al 2007), motility (Park et al 2014), differentiation program (Wamaitha et al 2015;Guye et al 2016), or even kill the cell outright . Synthetic intercellular signaling allows cell populations to make decisions and coordinate behaviors both locally (Sprinzak et al 2010;Matsuda et al 2012) and globally (Tabor et al 2009;Prindle et al 2011;Chen et al 2015b).…”