title: Age-Related Increase of EED Expression in Early Hematopoietic Progenitor Cells is Associated with Global Increase of the Histone Modification H3K27me3.
abstract: Human hematopoietic stem and progenitor cells (HSPCs) from umbilical cord blood exhibit higher differentiation potential and repopulation capacity compared to adult HSPCs. The molecular basis for these functional differences is currently unknown. Upon screening for epigenetic effector genes being differentially expressed in neonatal and adult HSPC subpopulations, the Polycomb Repressive Complex 2 (PRC2) member EED was identified. Even though EED is expressed at comparable amounts in neonatal and adult multipotent HSPCs, early adult lineage committed progenitors of the lymphomyeloid (LM) and erythromyeloid lineages expressed higher EED amounts than neonatal HPCs. We demonstrate that EED overexpression directly leads to higher H3K27me3 levels, a repressive histone modification that is mediated by the PRC2 complex. Quantitative analysis of H3K27me3 levels by FPLC-based ELISA revealed elevated levels in primary blood cells from adults. Besides quantitative changes, gene ontology analysis of the genome-wide H3K27me3 distribution revealed qualitative changes in adult HSPCs with elevated levels in genes associated with nonhematopoietic development pathways. In contrast, H3K4me3 which labels active chromatin was enriched on hematopoietic genes. In vitro differentiation of EED-transfected neonatal HSPCs revealed aberrant expression of the myelopoietic marker CD14, suggesting that EED affects the lymphoid versus myeloid decision processes within the lymphomyeloid lineage. This is in line with LM progenitors having the most pronounced differences in EED expression. Highlighting the dynamic roles of epigenetic modifications in human hematopoiesis, the present data demonstrate shifts in the PRC2-associated histone modification H3K27me3 from birth to adulthood.
authors.affiliation: 1 Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf , Medical Faculty, Düsseldorf, Germany .|2 Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University Düsseldorf , Medical Faculty, Düsseldorf, Germany .
authors.forename: Nina
authors.initials: N
authors.lastname: Graffmann
authors.affiliation: 2 Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University Düsseldorf , Medical Faculty, Düsseldorf, Germany .
authors.forename: Jens
authors.initials: J
authors.lastname: Brands
authors.affiliation: 3 Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen , Essen, Germany .
authors.forename: André
authors.initials: A
authors.lastname: Görgens
authors.affiliation: 3 Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen , Essen, Germany .|4 CAPES Foundation, Ministry of Education of Brazil , Brasília, Brazil .
authors.forename: Symone
authors.initials: S
authors.lastname: Vitoriano da Conceição Castro
authors.affiliation: 2 Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University Düsseldorf , Medical Faculty, Düsseldorf, Germany .
authors.forename: Simeon
authors.initials: S
authors.lastname: Santourlidis
authors.affiliation: 5 Institute of Forensic Medicine, Heinrich Heine University Düsseldorf , Medical Faculty, Düsseldorf, Germany .
authors.forename: Alexandra
authors.initials: A
authors.lastname: Reckert
authors.affiliation: 5 Institute of Forensic Medicine, Heinrich Heine University Düsseldorf , Medical Faculty, Düsseldorf, Germany .
authors.forename: Inga
authors.initials: I
authors.lastname: Michele
authors.affiliation: 5 Institute of Forensic Medicine, Heinrich Heine University Düsseldorf , Medical Faculty, Düsseldorf, Germany .
authors.forename: Stefanie
authors.initials: S
authors.lastname: Ritz-Timme
authors.affiliation: 2 Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University Düsseldorf , Medical Faculty, Düsseldorf, Germany .
authors.forename: Johannes C
authors.initials: JC
authors.lastname: Fischer
authors.affiliation: 1 Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University Düsseldorf , Medical Faculty, Düsseldorf, Germany .
authors.forename: James
authors.initials: J
authors.lastname: Adjaye
authors.affiliation: 2 Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University Düsseldorf , Medical Faculty, Düsseldorf, Germany .
authors.forename: Gesine
authors.initials: G
authors.lastname: Kögler
authors.affiliation: 3 Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen , Essen, Germany .
authors.forename: Bernd
authors.initials: B
authors.lastname: Giebel
authors.affiliation: 2 Institute for Transplantation Diagnostics and Cell Therapeutics, Heinrich Heine University Düsseldorf , Medical Faculty, Düsseldorf, Germany .
authors.forename: Markus
authors.initials: M
authors.lastname: Uhrberg
mesh_terms: D002460:Cell Line; D019070:Cell Lineage / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006657:Histones / Q000235:genetics* / Q000378:metabolism*; D000066449:Human Embryonic Stem Cells / Q000166:cytology*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*
chemical_list: C491488:EED protein, human; D006657:Histones; D063151:Polycomb Repressive Complex 2