SCL/TAL1 cooperates with Polycomb RYBP-PRC1 to suppress alternative lineages in blood-fated cells

Hedia Chagraoui, Maiken S. Kristiansen, Juan Pablo Ruiz, Ana Serra-Barros, Johanna Richter, Elisa Hall-Ponselé, Nicki Gray, Dominic Waithe, Kevin Clark, Philip Hublitz, Emmanouela Repapi, Georg Otto, Paul Sopp, Stephen Taylor, Supat Thongjuea, Paresh Vyas and Catherine Porcher ()
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Hedia Chagraoui: University of Oxford, John Radcliffe Hospital
Maiken S. Kristiansen: University of Oxford, John Radcliffe Hospital
Juan Pablo Ruiz: University of Oxford, John Radcliffe Hospital
Ana Serra-Barros: University of Oxford, John Radcliffe Hospital
Johanna Richter: University of Oxford, John Radcliffe Hospital
Elisa Hall-Ponselé: University of Oxford, John Radcliffe Hospital
Nicki Gray: University of Oxford, John Radcliffe Hospital
Dominic Waithe: University of Oxford, John Radcliffe Hospital
Kevin Clark: University of Oxford, John Radcliffe Hospital
Philip Hublitz: University of Oxford, John Radcliffe Hospital
Emmanouela Repapi: University of Oxford, John Radcliffe Hospital
Georg Otto: University of Oxford, John Radcliffe Hospital
Paul Sopp: University of Oxford, John Radcliffe Hospital
Stephen Taylor: University of Oxford, John Radcliffe Hospital
Supat Thongjuea: University of Oxford, John Radcliffe Hospital
Paresh Vyas: University of Oxford, John Radcliffe Hospital
Catherine Porcher: University of Oxford, John Radcliffe Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract During development, it is unclear if lineage-fated cells derive from multilineage-primed progenitors and whether active mechanisms operate to restrict cell fate. Here we investigate how mesoderm specifies into blood-fated cells. We document temporally restricted co-expression of blood (Scl/Tal1), cardiac (Mesp1) and paraxial (Tbx6) lineage-affiliated transcription factors in single cells, at the onset of blood specification, supporting the existence of common progenitors. At the same time-restricted stage, absence of SCL results in expansion of cardiac/paraxial cell populations and increased cardiac/paraxial gene expression, suggesting active suppression of alternative fates. Indeed, SCL normally activates expression of co-repressor ETO2 and Polycomb-PRC1 subunits (RYBP, PCGF5) and maintains levels of Polycomb-associated histone marks (H2AK119ub/H3K27me3). Genome-wide analyses reveal ETO2 and RYBP co-occupy most SCL target genes, including cardiac/paraxial loci. Reduction of Eto2 or Rybp expression mimics Scl-null cardiac phenotype. Therefore, SCL-mediated transcriptional repression prevents mis-specification of blood-fated cells, establishing active repression as central to fate determination processes.

Date: 2018
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DOI: 10.1038/s41467-018-07787-6

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