Department of Genetics, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21790-4. doi: 10.1073/pnas.1016306107. Epub 2010 Nov 22.
In yeast, Sir2 family proteins (sirtuins) regulate gene silencing, recombination, DNA repair, and aging via histone deacetylation. Most of the seven mammalian sirtuins (Sirt1-Sirt7) have been implicated as NAD(+)-dependent protein deacetylases with targets ranging from transcriptional regulators to metabolic enzymes. We report that neural-specific deletion of sirtuin 6 (Sirt6) in mice leads to postnatal growth retardation due to somatotropic attenuation through low growth hormone (GH) and insulin-like growth factor 1 (IGF1) levels. However, unlike Sirt6 null mice, neural Sirt6-deleted mice do not die from hypoglycemia. Instead, over time, neural Sirt6-deleted mice reach normal size and ultimately become obese. Molecularly, Sirt6 deletion results in striking hyperacetylation of histone H3 lysine 9 (H3K9) and lysine 56 (H3K56), two chromatin marks implicated in the regulation of gene activity and chromatin structure, in various brain regions including those involved in neuroendocrine regulation. On the basis of these findings, we propose that Sirt6 functions as a central regulator of somatic growth and plays an important role in preventing obesity by modulating neural chromatin structure and gene activity.
在酵母中，Sir2 家族蛋白（sirtuins）通过组蛋白去乙酰化来调节基因沉默、重组、DNA 修复和衰老。哺乳动物中的 7 种 sirtuins（Sirt1-Sirt7）大多被认为是 NAD(+)依赖的蛋白去乙酰酶，其靶标范围从转录调节因子到代谢酶。我们报告称，小鼠中神经元特异性的 Sirt6（Sirt6）缺失会导致生长迟缓，这是由于生长激素 (GH) 和胰岛素样生长因子 1 (IGF1) 水平降低导致的生长激素缺乏。然而，与 Sirt6 缺失小鼠不同的是，神经元 Sirt6 缺失的小鼠不会因低血糖而死亡。相反，随着时间的推移，神经元 Sirt6 缺失的小鼠会达到正常大小，并最终变得肥胖。从分子水平上看，Sirt6 的缺失导致组蛋白 H3 赖氨酸 9（H3K9）和赖氨酸 56（H3K56）的乙酰化显著增加，这两种染色质标记物与基因活性和染色质结构的调节有关，在包括参与神经内分泌调节的各种大脑区域中都是如此。基于这些发现，我们提出 Sirt6 作为体细胞生长的中央调节因子发挥作用，并通过调节神经染色质结构和基因活性，在预防肥胖方面发挥着重要作用。
