AN RNA-BINDING PROTEIN ASSOCIATES WITH HETEROCHROMATIC RNAS TO TRIGGER SILENCING

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 基因沉默是一种核心的细胞调控机制。一种在真核生物王国中保守的沉默形式涉及组蛋白H3赖氨酸9(H3K9)甲基化，HP1家族中识别这种修饰的蛋白质，以及有趣的RNAi机制。尽管这种机制具有保守性和重要性，但这种沉默是如何启动的，RNAi如何促进组蛋白甲基化，以及最终如何抑制基因表达，这些基本问题在很大程度上仍未得到解答。为了解决这些问题，我们最近将工作从组蛋白变异体H2A.Z和其他调控酿酒酵母沉默的分子(缺乏H3K9甲基化和RNAi系统)转移到高度易驯化的分裂酵母裂殖酵母Pombe中的沉默研究。在这项建议中，我们试图利用我们实验室已经进行的一系列分裂酵母的初步调查，以实现对基因沉默的机制理解。这项工作将使我们了解抑制性组蛋白甲基化，这是一种与人类癌症中肿瘤抑制基因失活密切相关的机制。公共卫生相关性：我们的工作重点是了解由抑制性组蛋白甲基化介导的基因沉默的机制。由于这种机制与肿瘤抑制基因在人类癌症中的失活密切相关，我们对这一保守过程的基本见解将为更多的肿瘤生物学应用研究提供信息。我们希望这将为重新激活肿瘤抑制基因的表达、阻止肿瘤细胞生长和/或诱导肿瘤细胞死亡的治疗方法的开发开辟新的途径。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Gene silencing is a core cellular regulatory mechnaism. One form of silencing, conserved across eukaryotic kingdoms, involves histone H3 lysine 9 (H3K9) methylation, proteins of the HP1 family that recognize this modification, and, intriguingly, the RNAi machinery. Despite the conservation and significance of this mechanism, the fundamental questions of how this type of silencing is initiated, how RNAi promotes histone methylation, and how repression of gene expression is ultimately effected remain largely unanswered. To address these issues, we recently shifted our efforts from studies of the histone variant H2A.Z and other molecules that regulate silencing in S. cerevisiae (which lacks both H3K9 methylation and RNAi systems) to studies of silencing in the highly tractable fission yeast Schizosaccharomyces pombe. In this proposal, we seek to capitalize on a series of preliminary investigations in fission yeast already carried out in our laboratory to achieve a mechanistic understanding of gene silencing. This work will inform our understanding of repressive histone methylation, a mechanism that has been strongly implicated in the inactivation of tumor suppressor genes in human cancers. PUBLIC HEALTH RELEVANCE: Our work focuses on understanding the mechanism of gene silencing mediated by repressive histone methylation. Since such mechanisms have been strongly implicated in the inactivation of tumor suppressor genes in human cancers, our fundamental insights into this conserved process will inform more applied studies of tumor biology. Our hope is that this will open up new avenues for the development of therapies that reactivate the expression of tumor suppressor genes and arrest growth and/or induce death of malignant cells.