title: Polycomb repressive complex 2 component Suz12 is required for hematopoietic stem cell function and lymphopoiesis.
abstract: Polycomb repressive complex 2 (PRC2) is a chromatin modifier that regulates stem cells in embryonic and adult tissues. Loss-of-function studies of PRC2 components have been complicated by early embryonic dependence on PRC2 activity and the partial functional redundancy of enhancer of zeste homolog 1 (Ezh1) and enhancer of zeste homolog 2 (Ezh2), which encode the enzymatic component of PRC2. Here, we investigated the role of PRC2 in hematopoiesis by conditional deletion of suppressor of zeste 12 protein homolog (Suz12), a core component of PRC2. Complete loss of Suz12 resulted in failure of hematopoiesis, both in the embryo and the adult, with a loss of maintenance of hematopoietic stem cells (HSCs). In contrast, partial loss of PRC2 enhanced HSC self-renewal. Although Suz12 was required for lymphoid development, deletion in individual blood cell lineages revealed that it was dispensable for the development of granulocytic, monocytic, and megakaryocytic cells. Collectively, these data reveal the multifaceted role of PRC2 in hematopoiesis, with divergent dose-dependent effects in HSC and distinct roles in maturing blood cells. Because PRC2 is a potential target for cancer therapy, the significant consequences of modest changes in PRC2 activity, as well as the cell and developmental stage-specific effects, will need to be carefully considered in any therapeutic context.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology and.
authors.forename: Stanley C W
authors.initials: SC
authors.lastname: Lee
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;
authors.forename: Sarah
authors.initials: S
authors.lastname: Miller
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;
authors.forename: Craig
authors.initials: C
authors.lastname: Hyland
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology and.
authors.forename: Maria
authors.initials: M
authors.lastname: Kauppi
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;
authors.forename: Marion
authors.initials: M
authors.lastname: Lebois
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia;
authors.forename: Ladina
authors.initials: L
authors.lastname: Di Rago
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology and.
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology and.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Kinkel
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology and.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Josefsson
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology and Department of Genetics, University of Melbourne, Parkville, VIC, Australia.
authors.forename: Marnie E
authors.initials: ME
authors.lastname: Blewitt
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology and.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Majewski
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia; Department of Medical Biology and.
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D005333:Fetus / Q000276:immunology / Q000502:physiology; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000502:physiology*; D038041:Lymphopoiesis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000502:physiology*
chemical_list: C494163:Suz12 protein, mouse; D063151:Polycomb Repressive Complex 2