TBX3 Directs Cell-Fate Decision toward Mesendoderm

Abstract

SummaryCell-fate decisions and pluripotency are dependent on networks of key transcriptional regulators. Recent reports demonstrated additional functions of pluripotency-associated factors during early lineage commitment. The T-box transcription factor TBX3 has been implicated in regulating embryonic stem cell self-renewal and cardiogenesis. Here, we show that TBX3 is dynamically expressed during specification of the mesendoderm lineages in differentiating embryonic stem cells (ESCs) in vitro and in developing mouse and Xenopus embryos in vivo. Forced TBX3 expression in ESCs promotes mesendoderm specification by directly activating key lineage specification factors and indirectly by enhancing paracrine Nodal/Smad2 signaling. TBX3 loss-of-function analyses in the Xenopus underline its requirement for mesendoderm lineage commitment. Moreover, we uncovered a functional redundancy between TBX3 and Tbx2 during Xenopus gastrulation. Taken together, we define further facets of TBX3 actions and map TBX3 as an upstream regulator of the mesendoderm transcriptional program during gastrulation.

MiR-93 Controls Adiposity via Inhibition of Sirt7 and Tbx3

“…In our search for putative stem cell-related targets that might explain the expansion of the early adipocyte precursor pool following suppression of miR-93, we identified the transcription factor Tbx3 as a candidate. Indeed, Tbx3 promotes mesendodermal differentiation during embryogenesis (Weidgang et al, 2013). Our data from fetuses in which Tbx3 was ablated in PDGFR cells support this notion and demonstrate a key role for Tbx3 in early adipocyte precursors.…”

NeuroD1 reprograms chromatin and transcription factor landscapes to induce the neuronal program

“…Our study further shows that NeuroD1 displaced TBX3 from its target sites to induce neuronal gene expression, suggesting that TBX3 functions in suppressing the neuronal lineage. In support of this model, a recent study showed that TBX3 drives cell fate specification toward the mesoendoderm (Weidgang et al , ). These observations suggest that TBX3 promotes the mesoendoderm lineage while suppressing the neuronal lineage and that the expression of NeuroD1 during neuronal development overrides TBX3's function.…”

“…Interestingly, many of the promoter URT were co‐occupied by UTF1 and TBX3 (Appendix Fig S5C). While UTF1 is an established contributor to the pluripotent state, we were intrigued to notice TBX3 at the repressed neuronal genes, as a recent study implicated TBX3 in the specification of mesoendoderm lineage (Weidgang et al , ). Importantly further, the chromatin at NeuroD1 target promoters was substantially less accessible compared with that of non‐target promoters (Fig A and B).…”

Inferring Cell-State Transition Dynamics from Lineage Trees and Endpoint Single-Cell Measurements

“…In accordance with previous work (Falco et al, 2007; Ivanova et al, 2006; Lu et al, 2011; Macfarlan et al, 2012; Niwa et al, 2009; Singer et al, 2014; Singh et al, 2007; Toyooka et al, 2008; Weidgang et al, 2013; Zalzman et al, 2010), we selected Esrrb, Tbx3, and, Zscan4 as potential cell state markers (also see STAR Methods). To better characterize their expression distributions, we simultaneously measured the mRNA copy number of Esrrb, Tbx3, and, Zscan4, in single ES cells using 3-color smFISH.…”

“…Tbx3 has been shown to destabilize pluripotency when lost or over-expressed. It also appears critical for mesendoderm specification, and its expression may change the global levels of DNA methylation in mouse ES cells (Dan et al, 2013; Ivanova et al, 2006; Lu et al, 2011; Niwa et al, 2009; Weidgang et al, 2013). However, it remains unclear how Tbx3 expression emerges dynamically from these states.…”