Cohesin Polycomb Interactions in Gene Regulation

拟议工作的长期目标是确定姐妹染色单体凝聚力蛋白是如何控制的。 基因转录。这将阐明某些人类遗传综合征的基础机制和 癌症。在拓扑结构上，粘附素包围姐妹染色单体，将它们结合在一起，直到细胞分裂。中等 粘附素活性的降低不会破坏染色单体的凝聚力，但会改变基因转录，导致不良反应 成长和发展。在多种癌症中，高粘附素活性与预后不良有关。 粘附素如何控制转录在很大程度上是未知的，但目前的证据认为，它参与了 直接在多个机制中。最近的发现证明了一种新的范式，在这种范式中， 粘附素和多梳抑制复合体1(PRC1)表观遗传沉默复合体全局控制两者 基因沉默和许多活性基因的转录。数据表明，粘附素直接促进了结合 其中PRC1阻止启动子上暂停的RNA聚合酶II(POL II) 过早地进入伸长阶段。他们还表明，活性基因上的粘附素隔离了PRC1， 从而控制有多少可用于基因沉默，并且Prc1限制了沉默时的粘附素结合 和活跃的基因。该提案的目标是测试这一新范式，并通过以下方式确定机制 其中粘附素和Prc1共同控制基因沉默和活性基因的转录。 拟议的研究结合了生化、遗传、基因组和生物物理方法来测试关键 对当前模型的预测。目标1测试了粘附素与PRC1物理相互作用的想法，以直接 促进Prc1与活性基因启动子的结合，并通过相互作用限制粘附素结合 具有粘附素加载或去除因子。AIM 2测试了PRC1防止暂停提前进入的想法 Pol II通过促进NELF和DSIF暂停因子或Pol II激酶活性而延长。对以下方面的见解 这些研究提供的粘附素和Prc1控制转录的机制应该表明 纠正遗传综合征和癌症中粘附素-Prc1失衡的新方法。

The long-term goal of the proposed work is to determine how sister chromatid cohesion proteins control gene transcription. This will illuminate mechanisms that underlie certain human genetic syndromes and cancers. Cohesin topologically encircles sister chromatids to hold them together until a cell divides. Moderate reductions in cohesin activity don't disrupt chromatid cohesion, but alter gene transcription, leading to poor growth and development. High cohesin activity is linked to poor prognosis in multiple cancers. How cohesin controls transcription is largely unknown, but current evidence argues that it participates directly in multiple mechanisms. Recent discoveries argue for a new paradigm in which a balance between cohesin and the Polycomb Repressive Complex 1 (PRC1) epigenetic silencing complex globally controls both gene silencing and transcription of many active genes. The data argue that cohesin directly facilitates binding of PRC1 to active genes, where PRC1 prevents paused RNA polymerase II (Pol II) at the promoter from prematurely entering into elongation. They also suggest that cohesin at active genes sequesters PRC1, thereby controlling how much is available for gene silencing, and that PRC1 limits cohesin binding at silenced and active genes. The goal of this proposal is to test this new paradigm, and determine the mechanisms by which cohesin and PRC1 together control both gene silencing and transcription of active genes. The proposed studies combine biochemical, genetic, genomic, and biophysical approaches to test key predictions of the current model. Aim 1 tests the ideas that cohesin physically interacts with PRC1 to directly facilitate PRC1 binding to active gene promoters, and that PRC1 limits cohesin binding through interactions with cohesin loading or removal factors. Aim 2 tests the idea that PRC1 prevents premature entry of paused Pol II into elongation by facilitating NELF and DSIF pausing factor or Pol II kinase activities. The insights into the mechanisms by which cohesin and PRC1 control transcription provided by these studies should suggest new methods for correcting cohesin-PRC1 imbalances in genetic syndromes and cancer.