title: Itga2b regulation at the onset of definitive hematopoiesis and commitment to differentiation.
abstract: Product of the Itga2b gene, CD41 contributes to hematopoietic stem cell (HSC) and megakaryocyte/platelet functions. CD41 expression marks the onset of definitive hematopoiesis in the embryo where it participates in regulating the numbers of multipotential progenitors. Key to platelet aggregation, CD41 expression also characterises their precursor, the megakaryocyte, and is specifically up regulated during megakaryopoiesis. Though phenotypically unique, megakaryocytes and HSC share numerous features, including key transcription factors, which could indicate common sub-regulatory networks. In these respects, Itga2b can serve as a paradigm to study features of both developmental-stage and HSC- versus megakaryocyte-specific regulations. By comparing different cellular contexts, we highlight a mechanism by which internal promoters participate in Itga2b regulation. A developmental process connects epigenetic regulation and promoter switching leading to CD41 expression in HSC. Interestingly, a similar process can be observed at the Mpl locus, which codes for another receptor that defines both HSC and megakaryocyte identities. Our study shows that Itga2b expression is controlled by lineage-specific networks and associates with H4K8ac in megakaryocyte or H3K27me3 in the multipotential hematopoietic cell line HPC7. Correlating with the decrease in H3K27me3 at the Itga2b Iocus, we find that following commitment to megakaryocyte differentiation, the H3K27 demethylase Jmjd3 up-regulation influences both Itga2b and Mpl expression.
authors.affiliation: Institute for Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. s.dumon@bham.ac.uk
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dumon
authors.forename: David S
authors.initials: DS
authors.lastname: Walton
authors.forename: Giacomo
authors.initials: G
authors.lastname: Volpe
authors.forename: Nicola
authors.initials: N
authors.lastname: Wilson
authors.forename: Emilie
authors.initials: E
authors.lastname: Dassé
authors.forename: Walter
authors.initials: W
authors.lastname: Del Pozzo
authors.forename: Josette-Renee
authors.initials: JR
authors.lastname: Landry
authors.forename: Bryan
authors.initials: B
authors.lastname: Turner
authors.forename: Laura P
authors.initials: LP
authors.lastname: O'Neill
authors.forename: Berthold
authors.initials: B
authors.lastname: Göttgens
authors.forename: Jon
authors.initials: J
authors.lastname: Frampton
mesh_terms: D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D004247:DNA / Q000378:metabolism; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006801:Humans; D039421:Integrin alpha2 / Q000378:metabolism*; D008533:Megakaryocytes / Q000166:cytology; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D040201:Platelet Membrane Glycoprotein IIb / Q000378:metabolism; D011401:Promoter Regions, Genetic; D053628:Receptors, Thrombopoietin / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: C056564:ITGA2B protein, human; D039421:Integrin alpha2; D040201:Platelet Membrane Glycoprotein IIb; D053628:Receptors, Thrombopoietin; D011994:Recombinant Proteins; C082218:MPL protein, human; D004247:DNA