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

Autor: Chagraoui H; Medical Research Council Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK., Kristiansen MS; Medical Research Council Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.; Medimmune, Granta Park, CB21 6GH, Cambridge, UK., Ruiz JP; Medical Research Council Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.; Haematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA., Serra-Barros A; Medical Research Council Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK., Richter J; Medical Research Council Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK., Hall-Ponselé E; Medical Research Council Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.; MRC Centre for Regenerative Medicine, SCRM Building, The University of Edinburgh, Edinburgh, EH16 4UU, UK., Gray N; Computational Biology Research Group, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK., Waithe D; Wolfson Imaging Centre, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK., Clark K; FACS Facility, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK., Hublitz P; Genome Engineering Facility, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK., Repapi E; Computational Biology Research Group, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK., Otto G; Medical Research Council Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.; Oxford National Institute for Health Research, Biomedical Research Centre, Haematology Theme, Oxford University Hospital, Oxford, OX3 9DU, UK.; Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK., Sopp P; FACS Facility, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK., Taylor S; Computational Biology Research Group, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK., Thongjuea S; Computational Biology Research Group, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.; Oxford National Institute for Health Research, Biomedical Research Centre, Haematology Theme, Oxford University Hospital, Oxford, OX3 9DU, UK., Vyas P; Medical Research Council Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.; Oxford National Institute for Health Research, Biomedical Research Centre, Haematology Theme, Oxford University Hospital, Oxford, OX3 9DU, UK., Porcher C; Medical Research Council Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK. catherine.porcher@imm.ox.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2018 Dec 18; Vol. 9 (1), pp. 5375. Date of Electronic Publication: 2018 Dec 18.
DOI: 10.1038/s41467-018-07787-6
Abstrakt: 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.
Databáze: MEDLINE