Vaquero Alejandro, Scher Michael, Erdjument-Bromage Hediye, Tempst Paul, Serrano Lourdes, Reinberg Danny
Howard Hughes Medical Institute, Division of Nucleic Acids Enzymology, Department of Biochemistry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Jersey 08854, USA.
Nature. 2007 Nov 15;450(7168):440-4. doi: 10.1038/nature06268.
In contrast to stably repressive, constitutive heterochromatin and stably active, euchromatin, facultative heterochromatin has the capacity to alternate between repressive and activated states of transcription. As such, it is an instructive source to understand the molecular basis for changes in chromatin structure that correlate with transcriptional status. Sirtuin 1 (SIRT1) and suppressor of variegation 3-9 homologue 1 (SUV39H1) are amongst the enzymes responsible for chromatin modulations associated with facultative heterochromatin formation. SUV39H1 is the principal enzyme responsible for the accumulation of histone H3 containing a tri-methyl group at its lysine 9 position (H3K9me3) in regions of heterochromatin. SIRT1 is an NAD+-dependent deacetylase that targets histone H4 at lysine 16 (refs 3 and 4), and through an unknown mechanism facilitates increased levels of H3K9me3 (ref. 3). Here we show that the mammalian histone methyltransferase SUV39H1 is itself targeted by the histone deacetylase SIRT1 and that SUV39H1 activity is regulated by acetylation at lysine residue 266 in its catalytic SET domain. SIRT1 interacts directly with, recruits and deacetylates SUV39H1, and these activities independently contribute to elevated levels of SUV39H1 activity resulting in increased levels of the H3K9me3 modification. Loss of SIRT1 greatly affects SUV39H1-dependent H3K9me3 and impairs localization of heterochromatin protein 1. These findings demonstrate a functional link between the heterochromatin-related histone methyltransferase SUV39H1 and the histone deacetylase SIRT1.
与稳定抑制性的组成型异染色质和稳定活性的常染色质不同，兼性异染色质具有在转录的抑制状态和激活状态之间交替的能力。因此，它是理解与转录状态相关的染色质结构变化的分子基础的一个有启发性的来源。沉默调节蛋白1（SIRT1）和异染色质蛋白3-9同源物1（SUV39H1）是负责与兼性异染色质形成相关的染色质调节的酶。SUV39H1是负责在异染色质区域积累在其赖氨酸9位置含有三甲基基团的组蛋白H3（H3K9me3）的主要酶。SIRT1是一种NAD+依赖的脱乙酰酶，其作用靶点是赖氨酸16位置的组蛋白H4（参考文献3和4），并通过一种未知机制促进H3K9me3水平的升高（参考文献3）。在这里，我们表明哺乳动物组蛋白甲基转移酶SUV39H1本身是组蛋白脱乙酰酶SIRT1的作用靶点，并且SUV39H1的活性受其催化SET结构域中赖氨酸残基266处的乙酰化调节。SIRT1直接与SUV39H1相互作用、招募并使其脱乙酰，并且这些活性独立地导致SUV39H1活性水平升高，从而导致H3K9me3修饰水平增加。SIRT1的缺失极大地影响了SUV39H1依赖的H3K9me3，并损害了异染色质蛋白1的定位。这些发现证明了异染色质相关组蛋白甲基转移酶SUV39H1和组蛋白脱乙酰酶SIRT1之间的功能联系。
