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MESP1 – Master of Mesendoderm?

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Review of “Genome-Wide Identification of MESP1 Targets Demonstrates Primary Regulation Over Mesendoderm Gene Activity” from Stem Cells by Stuart P. Atkinson

While the basic helix-loop-helix transcription factor Mesp1 is well known as a critical regulator of the cardiovascular system, several studies have suggested that Mesp1 may do much more. However, identifying downstream targets for Mesp1 has proved difficult, and so researchers from the laboratories of Yu Liu and Robert J. Schwartz (University of Houston, Texas, USA) decided to approach the task from another angle.

Their new study, published in Stem Cells, uses a genetic labelling strategy in embryonic stem cells (ESCs), and this has allowed them to discover a surprising role for Mesp1 – as a regulator of mesendoderm, the precursor to both mesoderm (specifying cardiac, blood, and bone cells) and endoderm (specifying foregut endoderm and the pancreas) [1].

The group’s strategy involved the creation of a mouse Mesp1 reporter ESC line which marks each cell with a permanent fluorescent marker following Mesp1 expression. Sorting and analysis of Mesp1-positive cells at different stages of differentiation of ESCs as embryoid bodies demonstrated a coordinated upregulation of genes classically associated with mesoderm and endoderm and not only genes from the cardiac lineage. Indeed, in-depth analysis of differentiation found the expression of key mesendodermal regulators (Mixl1, Pitx2, Gata4, Gata6, Wnt5a, Wnt5b, Sox17, and Foxa2 [See figure]) in Mesp1-positive cells before the appearance of differentiated cell types such as cardiac progenitors or myocytes, overall suggesting that Mesp1-positive cells represented a mesendodermal progenitor.

The study then combined Mesp1-chromatin immunoprecipitation (ChIP) and next generation sequencing technology to show that Mesp1 activated mesendoderm-associated factors through binding to E-box DNA response element variants. Chromatin analysis associated Mesp1 binding with increases in the trimethylation of lysine 4 H3 at promoter-proximal regions and acetylation of lysine 27 H3 at distal enhancer regions, suggesting that Mesp1 binding promotes the alteration of the chromatin configuration of target genes to promote an expression-competent state.

Can we now crown Mesp1 as the master of mesendoderm instead of the coordinator of the cardiovascular system? The strategy applied here, which avoids overexpression and the possible inclusion of multiple false-positives, strongly suggests that Mesp1 coordinates this bi-potential developmental pathway and highlights important factors which may be used in the future to improve reprogramming efforts towards generating mesendodermal cells and tissues for replacement therapy. The authors point to studies to understand how Mesp1 mediates the alterations to the chromatin environment and how this affects the expression of target genes as the next chapter of their intriguing research. 

References

  1. Soibam B, Benham A, Kim J, et al. Genome-Wide Identification of MESP1 Targets Demonstrates Primary Regulation Over Mesendoderm Gene Activity. Stem Cells 2015;33:3254-3265.