title: Sirt1 ablation promotes stress-induced loss of epigenetic and genomic hematopoietic stem and progenitor cell maintenance.
abstract: The (histone) deacetylase Sirt1 is a mediator of genomic and epigenetic maintenance, both of which are critical aspects of stem cell homeostasis and tightly linked to their functional decline in aging and disease. We show that Sirt1 ablation in adult hematopoietic stem and progenitor cells (HSPCs) promotes aberrant HSPC expansion specifically under conditions of hematopoietic stress, which is associated with genomic instability as well as the accumulation of DNA damage and eventually results in a loss of long-term progenitors. We further demonstrate that progenitor cell expansion is mechanistically linked to the selective up-regulation of the HSPC maintenance factor and polycomb target gene Hoxa9. We show that Sirt1 binds to the Hoxa9 gene, counteracts acetylation of its histone target H4 lysine 16, and in turn promotes polycomb-specific repressive histone modification. Together, these findings demonstrate a dual role for Sirt1 in HSPC homeostasis, both via epigenetic regulation of a key developmental gene and by promoting genome stability in adult stem cells.
authors: Mouse Cancer Genetics Program, SAIC-Frederick, Inc, Frederick National Laboratory, National Cancer Institute, Frederick, MD 21702, USA.
authors: Satyendra K
authors: SK
authors: Singh
authors: Carrie A
authors: CA
authors: Williams
authors: Kimberly
authors: K
authors: Klarmann
authors: Sandra S
authors: SS
authors: Burkett
authors: Jonathan R
authors: JR
authors: Keller
authors: Philipp
authors: P
authors: Oberdoerffer
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D019610:Cytoprotection / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D044127:Epigenesis, Genetic; D017353:Gene Deletion; D056426:Genetic Loci / Q000235:genetics; D016678:Genome / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D011485:Protein Binding / Q000235:genetics; D056564:Sirtuin 1 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D013312:Stress, Physiological / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D002843:Chromatin; D006657:Histones; D018398:Homeodomain Proteins; D016159:Tumor Suppressor Protein p53; C097899:homeobox protein HOXA9; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
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