title: Per2 induction limits lymphoid-biased haematopoietic stem cells and lymphopoiesis in the context of DNA damage and ageing.
abstract: Ageing-associated impairments in haemato-lymphopoiesis are associated with DNA damage accumulation and reduced maintenance of lymphoid-biased (Ly-biased) compared with myeloid-biased (My-biased) haematopoietic stem cells (HSCs). Here, in vivo RNAi screening identifies period circadian clock 2 (Per2) as a critical factor limiting the maintenance of HSCs in response to DNA damage and ageing. Under these conditions, Per2 is activated predominantly in Ly-biased HSCs and stimulates DNA damage signalling and p53-dependent apoptosis in haematopoietic cells. Per2 deletion ameliorates replication stress and DNA damage responses in haematopoietic cells, thereby improving the maintenance of Ly-biased HSCs, lymphopoiesis, and immune function in ageing mice without increasing the accumulation of DNA damage. Per2-deficient mice retain Batf/p53-dependent induction of differentiation of HSCs in response to DNA damage and exhibit an elongated lifespan. Together, these results identify Per2 as a negative regulator of Ly-biased HSCs and immune functions in response to DNA damage and ageing.
authors.affiliation: Research Group on Stem Cell Aging, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Research Group on Stem Cell Aging, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Morita
authors.affiliation: Research Group on Stem Cell Aging, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany.
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.affiliation: Institute for Medical Microbiology, University Hospital Münster, Domagkstraße 10, 48149 Münster, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Niemann
authors.affiliation: Institute of Medical Microbiology, Jena University Hospital (UKJ), 07747 Jena, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Löffler
authors.affiliation: Research Group on Stem Cell Aging, Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstr. 11, 07745 Jena, Germany.|Research Group on Molecular Aging, Faculty of Medicine, Friedrich-Schiller-University, 07745 Jena, Germany.
authors.forename: K Lenhard
authors.initials: KL
authors.lastname: Rudolph
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D053264:B-Cell Activating Factor / Q000378:metabolism; D015153:Blotting, Western; D002454:Cell Differentiation; D002469:Cell Separation; D016922:Cellular Senescence; D004249:DNA Damage; D004261:DNA Replication; D005455:Fluorescent Antibody Technique; D017353:Gene Deletion; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006720:Homozygote; D007109:Immunity; D008214:Lymphocytes / Q000166:cytology*; D038041:Lymphopoiesis; D018345:Mice, Knockout; D056950:Period Circadian Proteins / Q000378:metabolism*; D013312:Stress, Physiological; D059506:Telomere Shortening; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D053264:B-Cell Activating Factor; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; C505720:Tnfsf13b protein, mouse; D016159:Tumor Suppressor Protein p53