Eomes and Brachyury control pluripotency exit and germ-layer segregation by changing the chromatin state

Abstract

The first lineage specification of pluripotent mouse epiblast segregates neuroectoderm (NE) from mesoderm and endoderm (ME) by currently poorly understood mechanisms. Here we demonstrate that the induction of any ME-gene programs critically relies on the T-box (Tbx) transcription factors Eomes and Brachyury that concomitantly repress pluripotency and NE gene programs. Tbx-deficient cells retain pluripotency and differentiate to NE lineages despite the presence of ME-inducing signals TGFb/Nodal and WNT. Pluripotency and NE gene networks are additionally repressed by Tbx-induced ME factors, demonstrating a remarkable redundancy in program regulation to safeguard mutually exclusive lineage specification. Chromatin analyses revealed that accessibility of ME-gene enhancers depends on Tbx-binding, while NE-gene enhancers are accessible and activation-primed already at pluripotency state. This asymmetry of chromatin landscape thus explains the default differentiation of pluripotent cells to NE in the absence of MEinduction mediated through the activating and repressive functions of early Tbx factors Eomes and Brachyury.

Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers

“…Hence, we deduced that differentiation abnormality might occur at mesendoderm stage, a transient stage before mesoderm formation. It has been reported that Eomes and T are mesendoderm pioneer driving factors that contribute to specify mesendoderm lineage ( 37 ). Checking the expression of Eomes and T by real-time PCR revealed significantly lower expression of these genes in day 1 Mst KO EBs than wild type EBs.…”

Pluripotency factors determine gene expression repertoire at zygotic genome activation

“…In Xenopus, maternal Foxh1, together with two other maternal factors, bind to the endodermal enhancers prior to ZGA and primes them for zygotic activity (Charney et al, 2017;Paraiso et al, 2019). In mouse, Eomesodermin, together with Brachyury, are the solely responsible factors for establishing the competence for activation of mesodermal enhancers, and repress pluripotency and neuroectodermal programs, driven by Pou5f1 and Sox2 (Tosic et al, 2019).…”

Human ES Cell Culture Conditions Fail to Preserve the Mouse Epiblast State

“…AA/F2 treatment for 6 days resulted in the upregulation of endoderm (Sox17 and Gata6) and pos-terior mesoderm markers (Tbx6 and Msgn1) (Figures 4(a) and 4(b), S3), reflecting on a mixed population of cells. In the epiblast, while high activin/nodal signaling supports endoderm differentiation [18,44], WNT/β-catenin supports posterior PS genes [45]. Both these pathways were active in the AA/F2-6D cells (Figure 3(a)), and at this stage, T was highly expressed (Figures 2(c)-2(e)), with considerable population of the cells expressing T (Figure 4(c)).…”

“…Several signaling pathways play crucial roles in this rearrangement process, such as TGFβ/activin/nodal, WNT/β-catenin, and FGF/ERK/MAPK signaling pathways [13][14][15]. The collaborative interaction between various transcription factors, such as the T-box transcription factors (Tbx) T and Eomes with the key markers of mesoderm and endoderm initiate this differentiation process [16][17][18].…”