Scl Represses Cardiomyogenesis in Prospective Hemogenic Endothelium and Endocardium

Abstract

Summary Endothelium in embryonic hematopoietic tissues generates hematopoietic stem/progenitor cells; however, it is unknown how its unique potential is specified. We show that transcription factor Scl/Tal1 is essential for both establishing the hematopoietic transcriptional program in hemogenic endothelium and preventing its misspecification to a cardiomyogenic fate. Scl−/− embryos activated a cardiac transcriptional program in yolk sac endothelium, leading to the emergence of CD31+Pdgfrα+ cardiogenic precursors that generated spontaneously beating cardiomyocytes. Ectopic cardiogenesis was also observed in Scl−/− hearts, where the disorganized endocardium precociously differentiated into cardiomyocytes. Induction of mosaic deletion of Scl in Sclfl/fl Rosa26Cre-ERT2 embryos revealed a cell-intrinsic, temporal requirement for Scl to prevent cardiomyogenesis from endothelium. Scl−/− endothelium also upregulated the expression of Wnt antagonists, which promoted rapid cardiomyocyte differentiation of ectopic cardiogenic cells. These results reveal unexpected plasticity in embryonic endothelium such that loss of a single master regulator can induce ectopic cardiomyogenesis from endothelial cells.

Analysis of chromatin-state plasticity identifies cell-type–specific regulators of H3K27me3 patterns

“…5 A-C). TAL1 is commonly known as a transcriptional activator in various hematopoietic lineages (39), although a role for gene repression has recently been described in a different cellular context (embryonic endothelium) (45). Our analysis suggested that TAL1 might also contribute to transcriptional repression in hematopoietic cells by modulating the activity of poised enhancers.…”

“…One of the most enriched GO biological processes was "regulation of heart contraction" [false-discovery rate (FDR) q-value = 1.1E-3], and one of the strongly associated mouse phenotypes was "congestive heart failure" (FDR q-value = 7.4E-4) (SI Appendix, Table S4). Interestingly, in the aforementioned study (45), the genes repressed by TAL1 were also associated with cardiomyogenesis. Despite the differences between the two model systems, we observed a significant overlap (58 of 965, P = 5.2E-6) between the genes harboring a poised enhancer in ProE cells and those up-regulated by TAL1 depletion in embryonic endothelium (45).…”

A short history of hemogenic endothelium

“…The transcription factor SCL is critically required for establishing hemogenic endothelium [50,[87][88][89]. Importantly, SCL is not required once the hemogenic endothelium has formed, placing it upstream of Runx1 [28,50,90].…”

“…Importantly, SCL is not required once the hemogenic endothelium has formed, placing it upstream of Runx1 [28,50,90]. Recently, loss of SCL was shown to initiate a cardiac-related transcriptional program in the yolk sac, indicating that SCL expression represses the cardiac program [89]. Conditional deletion of SCL indicated that this occurs early in development, possibly already in the hematopoietic-fated SCL expressing mesoderm.…”

Early Exposure of Murine Embryonic Stem Cells to Hematopoietic Cytokines Differentially Directs Definitive Erythropoiesis and Cardiomyogenesis in Alginate Hydrogel Three-Dimensional Cultures

“…During embryogenesis, hematopoietic cells originate from the lateral plate mesoderm in an ordered program of development occurring in conjunction with cells of the cardiovascular system and share a common precursor, the hemangioblast [8][9][10][11]. The study of the hemangioblast, hemogenic endothelial cells and endothelialto-hematopoietic transition [12][13][14] is critical to the understanding of related pathologies and for the development of a robust and reliable in vitro method of ESC differentiation toward cells, such as red blood cells (RBCs), which may be used in future clinical translational protocols [15][16][17].…”