Mouse Cancer Genetics Program, SAIC-Frederick, Inc, Frederick National Laboratory, National Cancer Institute, Frederick, MD 21702, USA.
J Exp Med. 2013 May 6;210(5):987-1001. doi: 10.1084/jem.20121608. Epub 2013 Apr 29.
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.
（组蛋白）去乙酰化酶 Sirt1 是基因组和表观遗传维持的介质，这两者都是干细胞动态平衡的关键方面，与衰老和疾病中干细胞功能下降密切相关。我们表明，在造血应激的情况下，成年造血干细胞和祖细胞（HSPC）中的 Sirt1 缺失会促进异常的 HSPC 扩增，这与基因组不稳定性以及 DNA 损伤的积累有关，最终导致长期祖细胞的丧失。我们进一步证明，祖细胞扩增在机制上与 HSPC 维持因子和多梳靶基因 Hoxa9 的选择性上调有关。我们表明，Sirt1 结合到 Hoxa9 基因上，拮抗其组蛋白靶标 H4 赖氨酸 16 的乙酰化，进而促进多梳特异性抑制性组蛋白修饰。这些发现共同表明 Sirt1 在 HSPC 动态平衡中具有双重作用，既通过对关键发育基因的表观遗传调控，也通过促进成年干细胞的基因组稳定性。
