The gene regulatory functions of condensin

项目总结 染色质的结构和组织是建立适合发育的基因表达的关键 每种细胞类型的程序，以及这些过程中的异常会导致发育异常和 疾病。我们研究计划的长期目标是定义一台专门的分子机器如何调用 凝聚素可以重组染色体，调节间期基因，促进染色体的发育。 有丝分裂中的分离。据报道，小头畸形症和各种不同疾病的患者存在凝聚素突变。 癌症。因此，该项目的研究结果将与人类健康直接相关。凝集素复合体 从酵母到人类都是保守的，虽然它们在有丝分裂中的作用相对明确，但它们在 间期基因调控还不是很清楚。X染色体全基因表达的调控。 Elgans为我们提供了一个揭示凝聚素的间期作用的机会。在这个有机体中，在一个过程中 被称为性染色体剂量补偿的一种特殊的凝集素复合体结合两条X染色体 XX个雌雄同体基因表达下调一半，从而平衡X连锁基因的表达 在两性之间。凝聚素介导的基因抑制涉及改变X染色体的结构 多个水平，包括组蛋白的翻译后修饰，染色质纤维的环化， 染色体紧凑和核组织。第一个主要项目将确定基因突变如何 与其有丝分裂作用相比，保守结构域影响凝聚素的间期作用。美国政府的影响 已知在有丝分裂中调节凝集素活性的磷酸化也将被研究。这个 第二个项目集中在组蛋白修饰物与凝集素协同作用的过程中的作用 剂量补偿。这些组蛋白修饰物在生殖系中执行额外的功能。该项目将 描述这种细胞机制的双重功能，以揭示如何利用相同的活动 在不同的组织中完成不同的生物功能。第三个项目考察了发育调节器如何 可以使性染色体剂量补偿与发育转变相协调。界定法规 关键剂量补偿蛋白在两个关键的转变，失去多能状态，然后终止 分化，将揭示这些过程之间的机械联系。精确的基因组编辑技术 组织和发育阶段特定的蛋白质消耗技术将被用来揭示 凝聚素在基因调控中的作用机制及调控。最先进的显微技术 将与基因组学方法和生物信息学相结合来鉴定染色体和染色质结构 与基因抑制有关的变化。

PROJECT SUMMARY Chromatin structure and organization are critical to establishing developmentally appropriate gene expression programs for each cell type, and aberrations in these processes lead to developmental abnormalities and disease. Our research program’s long-term goal is to define how a specialized molecular machine called condensin can restructure chromosomes to regulate genes in interphase as well as to promote chromosome segregation in mitosis. Condensin mutations have been reported in patients with microcephaly and various cancers. Therefore, findings from this project will have direct relevance to human health. Condensin complexes are conserved from yeast to human, and while their roles in mitosis are relatively well defined, their function in interphase gene regulation is not well understood. Regulation of X chromosome-wide gene expression in C. elegans provides us with an opportunity to uncover condensin’s interphase roles. In this organism, in a process called sex chromosome dosage compensation, a specialized condensin complex binds both X chromosomes of XX hermaphrodites to downregulate gene expression by half thereby equalizing X-linked gene expression between the sexes. Condensin-mediated gene repression involves altering X chromosome structure on multiple levels, including posttranslational modifications of histones, looping of the chromatin fiber, chromosome compaction, and nuclear organization. The first major project will determine how mutations in conserved domains affect condensin’s interphase roles compared to its mitotic roles. The effect of the phosphorylation, which is known to modulate condensin’s activity in mitosis, will also be investigated. The second project centers on the roles of histone modifiers which cooperate with condensin in the process of dosage compensation. These histone modifiers perform additional functions in the germline. The project will characterize the dual functionality of this cellular machinery to reveal how the same activity can be co-opted to fulfill different biological functions in different tissues. The third project examines how developmental regulators can coordinate sex chromosome dosage compensation with developmental transitions. Defining the regulation of key dosage compensation proteins at two key transitions, loss of the pluripotent state and then terminal differentiation, will reveal the mechanistic link between these processes. Precise genome editing techniques and tissue and developmental stage-specific protein depletion techniques will be employed to reveal the mechanism of action and regulation of condensin in gene regulation. State-of-the art microscopy techniques will be combined with genomic methods and bioinformatics to identify chromosome and chromatin structure changes that are linked to gene repression.