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

• Published in: Nature communications Vol. 9; no. 1; pp. 5375 - 17
• Main Authors: Chagraoui, Hedia, Kristiansen, Maiken S, Ruiz, Juan Pablo, Serra-Barros, Ana, Richter, Johanna, Hall-Ponselé, Elisa, Gray, Nicki, Waithe, Dominic, Clark, Kevin, Hublitz, Philip, Repapi, Emmanouela, Otto, Georg, Sopp, Paul, Taylor, Stephen, Thongjuea, Supat, Vyas, Paresh, Porcher, Catherine
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 18.12.2018; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Blood; Cell Differentiation - physiology; Cell fate; Cell Line; Cell Lineage - physiology; Cell Separation - methods; Embryo, Mammalian; Flow Cytometry - methods; Gene expression; Gene Expression Regulation, Developmental - physiology; Gene silencing; Genomes; Heart; Histone Code - physiology; Mesoderm; Mesoderm - cytology; Mesoderm - physiology; Mice; Mouse Embryonic Stem Cells; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phenotypes; Polycomb group proteins; Polycomb Repressive Complex 1 - metabolism; Polycomb-Group Proteins - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; RNA, Small Interfering - metabolism; Specifications; T-Cell Acute Lymphocytic Leukemia Protein 1 - genetics; T-Cell Acute Lymphocytic Leukemia Protein 1 - metabolism; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-07787-6

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.