RNAi and Epigenetic Control of Higher-Order Chromatin As

我们实验室的研究集中在高阶染色质组装的表观遗传控制上。高阶染色体结构的动态调节支配着从基因表达模式的稳定遗传到保持基因组完整性所必需的全局染色体结构的其他方面的各种细胞过程。我们早期的研究揭示了导致裂殖酵母粟酒裂殖酵母异染色质结构组装的分子事件序列。我们发现，共价修饰组蛋白尾部的脱乙酰基酶和甲基转移酶的活动一致行动，以建立“组蛋白代码”的异染色质结构的组装所必需的。此外，我们发现，不同的位点特异性组蛋白H3甲基化模式决定了染色体的组织成离散的结构和功能域。在赖氨酸9处甲基化的组蛋白H3严格地定位于沉默异染色质区域，而在赖氨酸4处甲基化的H3，仅几个氨基酸远，特异于周围的活性常染色质区域。我们继续关注组蛋白修饰的作用和识别特定组蛋白修饰模式的因子（如特异性结合组蛋白H3在赖氨酸9处甲基化的染色体结构域蛋白Swi6）在高阶染色质结构组装中的作用，并在理解高阶染色质组装机制方面取得了重大进展。更重要的是，我们提供的证据表明，RNA干扰（RNAi），即双链RNA沉默同源基因，在靶向异染色质复合物在基因组中的特定位置发挥关键作用。RNAi和异染色质组装之间的联系在包括哺乳动物在内的高等真核生物中是保守的，并且对人类生物学和包括癌症在内的疾病具有广泛的影响。

Research in our laboratory is focused on the epigenetic control of higher-order chromatin assembly. The dynamic regulation of higher-order chromosome structure governs diverse cellular processes ranging from stable inheritance of gene expression patterns to other aspects of global chromosome structure essential for preserving genomic integrity. Our earlier studies revealed sequence of molecular events leading to the assembly of heterochromatic structures in the fission yeast Schizosaccharomyces pombe. We found that covalent modifications of histone tails by deacetylase and methyltransferase activities act in concert to establish the "histone code" essential for assembly of heterochromatic structures. Moreover, we showed that distinct site-specific histone H3 methylation patterns dictate the organization of chromosomes into discrete structural and functional domains. Histone H3 methylated at lysine 9 is strictly localized to silent heterochromatic regions whereas H3 methylated at lysine 4, only a few amino acids away, is specific to the surrounding active euchromatic regions. We have continued to focus on the role of histone modifications and the factors that recognize specific histone modifications patterns (such as a chromodomain protein Swi6 that specifically binds histone H3 methylated at lysine 9) in the assembly of higher-order chromatin structures and have made significant progress in understanding the mechanism of higher-order chromatin assembly. More importantly, we provided evidence showing that RNA interference (RNAi), whereby double-stranded RNAs silence cognate genes, plays a critical role in targeting of heterochromatin complexes to specific locations in the genome. The link between RNAi and heterochromatin assembly is conserved in higher eukaryotes including mammals and has broad implications for human biology and disease including cancer.