<i>Eomes</i>restricts<i>Brachyury</i>functions at the onset of mammalian gastrulation

Schüle, Katrin M.; Weckerle, Jelena; Probst, Simone; Wehmeyer, Alexandra E.; Zissel, Lea; Schröder, Chiara M.; Tekman, Mehmet; Kim, Gwang-Jin; Schlägl, Inga-Marie; Sagar,; Arnold, Sebastian J.

doi:10.1101/2023.01.27.525830

Cited by 5 publications

(5 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As opposed to NMP populations which require TBXT for mesoderm differentiation (Gouti et al ., 2017; Koch et al ., 2017), we demonstrated that early PS populations do not require TBXT for the initial establishment of a relatively anterior mesoderm identity. This result is in agreement with studies showing that another T-box factor, EOMES, primarily drives mesoderm differentiation at this stage of development (Schüle et al ., 2023). However, we also discovered that TBXT is not dispensable at this early stage, as its expression directly influences the timing of EMT and therefore the ability of the nascent mesoderm cells to properly acquire a migratory mesenchymal character.…”

Section: Discussionsupporting

confidence: 93%

TBXT dose sensitivity and the decoupling of nascent mesoderm specification from EMT progression in 2D human gastruloids

Bulger,

Muncie-Vasic,

Libby

et al. 2023

Preprint

View full text Add to dashboard Cite

In the nascent mesoderm, levels of Brachyury (TBXT) expression must be precisely regulated to ensure cells exit the primitive streak and pattern the anterior-posterior axis, but how this varying dosage informs morphogenesis is not well understood. In this study, we define the transcriptional consequences of TBXT dose reduction during early human gastrulation using human induced pluripotent stem cell (hiPSC)-based models of gastrulation and mesoderm differentiation. Multiomic single-nucleus RNA and single-nucleus ATAC sequencing of 2D gastruloids comprised of WT, TBXT heterozygous (TBXT-Het), or TBXT null (TBXT-KO) hiPSCs reveal that varying TBXT dosage does not compromise a cell’s ability to differentiate into nascent mesoderm, but that the loss of TBXT significantly delays the temporal progression of the epithelial to mesenchymal transition (EMT). This delay is dependent on TBXT dose, as cells heterozygous for TBXT proceed with EMT at an intermediate pace relative to WT or TBXT-KO. By differentiating iPSCs of the allelic series into nascent mesoderm in a monolayer format, we further illustrate that TBXT dose directly impacts the persistence of junctional proteins and cell-cell adhesions. These results demonstrate that EMT progression can be decoupled from the acquisition of mesodermal identity in the early gastrula and shed light on the mechanisms underlying human embryogenesis.

show abstract

Section: Discussionsupporting

confidence: 93%

TBXT dose sensitivity and the decoupling of nascent mesoderm specification from EMT progression in 2D human gastruloids

Bulger,

Muncie-Vasic,

Libby

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…1hi). This is consistent with their distinct roles in posterior and anterior primitive streak, respectively, as BMP signaling is higher on the colony edge which thereby resembles the posterior of the embryo 9,15,16 . Heterogeneity at the single cell level increased over time and different PS markers lost the strong correlation they exhibit at 48h (Fig.…”

Section: Resultssupporting

confidence: 77%

Extended culture of 2D gastruloids to model human mesoderm development

Chen,

Khan,

et al. 2024

Preprint

View full text Add to dashboard Cite

Micropatterned human pluripotent stem cells (hPSCs) treated with BMP4 (2D gastruloids) are among the most widely used stem cell models for human gastrulation. Due to its simplicity and reproducibility, this system is ideal for high throughput quantitative studies of tissue patterning and has led to many insights into the mechanisms of mammalian gastrulation. However, 2D gastruloids have only been studied up to 48h. Here we extended this system to 96h. We discovered a phase of highly reproducible morphogenesis during which directed migration from the primitive streak-like region gives rise to a mesodermal layer beneath an epiblast-like layer. Multiple types of mesoderm arise with striking spatial organization including lateral mesoderm-like cells on the colony border and paraxial mesoderm-like further inside the colony. Single cell transcriptomics showed strong similarity of these cells to mesoderm in human and non-human primate embryos. However, our data suggest that the annotation of the reference human embryo may need to be revised. This illustrates that extended culture of 2D gastruloids provides a powerful model for human mesoderm differentiation and morphogenesis.

show abstract

“…In the absence of Tbx TF activities ME enhancers remain inaccessible and ME gene programs silent. Eomes dominates early phases of embryonic ME specification, followed by partially overlapping activities of the related Tbx factor Brachyury during formation of more posterior/axial mesoderm derivatives 36 . The Tbx TF- and SWI/SNF- dependent gain of accessibility creates competence for ME gene programs.…”

Section: Discussionmentioning

confidence: 99%

“…3a, b). In these cells the closely related, but later acting Tbx TF Brachyury is additionally deleted, since Brachyury gains premature functions in, and partially compensates for the absence of Eomes 36 . dKO cells fail to specify ME cell lineages 8 as confirmed by comparative RNA-seq of WT and dKO EBs at d3 (adjusted P≤0.05, log 2 (FC)≥2; Extended Data Fig.…”

Section: Main Textmentioning

confidence: 99%

An EOMES induced epigenetic deflection initiates lineage commitment at mammalian gastrulation

Schröder

Zissel

Mersiowsky

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Different cell types are determined by cell lineage-specific transcriptional programmes and by epigenetic regulation of chromatin. Yet, the functional relationships between dynamically expressed transcription factors (TFs) and chromatin changes guiding lineage specification often remain elusive. First mammalian embryonic lineages segregate when pluripotent cells become committed to either Mesoderm and Endoderm (ME) or Neuroectoderm (NE). NE forms by default in the absence of signalling-induced ME specification, resulting from global asymmetries in chromatin state favouring NE gene programme activation as recently demonstrated. In this study, we unravel the initiation of ME lineage specification by the genome-wide, de novo formation of chromatin accessibility at ME enhancers that epigenetically deflects pluripotent cells from default NE differentiation. The Tbx TF Eomes, previously considered a transcriptional regulator, acts as global chromatin organizer that establishes ME lineage competence. EOMES recruits the canonical ATP-dependent chromatin remodelling complex SWI/SNF to broadly generate the chromatin-accessible ME enhancer landscape. This lineage competence is generated independently of ME gene transcription that fully depends on ME-inducing signalling pathways including Wnts and TGFβ/NODAL. This study thus resolves the successive steps of ME lineage differentiation by globally establishing chromatin accessibility for lineage competence, followed by signal-encoded transcriptional regulation of different ME lineage-defining gene programmes.

show abstract

EomesrestrictsBrachyuryfunctions at the onset of mammalian gastrulation

Cited by 5 publications

References 71 publications

TBXT dose sensitivity and the decoupling of nascent mesoderm specification from EMT progression in 2D human gastruloids

TBXT dose sensitivity and the decoupling of nascent mesoderm specification from EMT progression in 2D human gastruloids

Extended culture of 2D gastruloids to model human mesoderm development

An EOMES induced epigenetic deflection initiates lineage commitment at mammalian gastrulation

Contact Info

Product

Resources

About