Epigenetic regulation of transcriptional programming

转录编程的表观遗传调控

基本信息

批准号：
10398124
负责人：
Mitzi I Kuroda
金额：
$ 71.76万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2024-04-30
项目状态：
已结题

项目摘要

PROJECT SUMMARY The genomes of higher organisms are highly annotated by specific chromosomal proteins and histone modifications along active genes, regulatory elements, or silent regions. This annotation is critical for proper cell type specification, and an ongoing challenge is to decipher the rules that establish and maintain chromatin organization. My laboratory focuses on analysis of chromatin regulatory complexes, based on their central importance in development and disease, the intriguing hypotheses raised by our recent studies, and our ability to use new approaches to probe chromatin protein interactions with precision. Historically, we have made significant contributions to understanding the targeting and spreading of chromatin domains, and currently we are probing the ability of chromatin factors to poise genes for key regulatory decisions that specify cell type. Our current studies focus on the Polycomb group (PcG) proteins, and due to the high conservation of this key regulatory system we move between fly embryos and human embryonic stem cells with ease. We are developing a model in which key regulatory genes are universally ‘poised’ early in development via occupancy of composite protein complexes of Polycomb Repressive Complex 1 (PRC1) and classical co-activators. These ‘bivalent’ protein complexes may resolve into full activation or repression, depending on the cell type-specific expression, binding, and function of transcription factors. We speculate that transcription factors may bind relatively promiscuously, but still execute precise regulatory decisions, when they influence the local acetylation/deacetylation state at these predetermined sites. Our speculative model is based on strong proteomic evidence that PRC1 strongly interacts with classic co-activators, dBRD4 and dMOZ/MORF, captured on chromatin during embryogenesis in Drosophila, and by analogous co-occupancy of CBX7, RING2 (subunits of PRC1), and BRD1 (a subunit of MOZ/MORF) in human embryonic stem cells. We believe that we are on the cusp of understanding chromatin transitions and transcriptional programming at a mechanistic level. These studies also synergize with our molecular dissection of aberrant chromatin complexes that drive human cancers.

项目概要高等生物的基因组由特定的染色体蛋白高度注释，该注释是沿活性基因、调控元件或沉默区域的组蛋白修饰。对于正确的细胞类型规范至关重要，而持续的挑战是破译细胞类型的规则建立和维护染色质组织我的实验室专注于染色质分析。调节复合物，基于它们在发育和疾病中的核心重要性，有趣的我们最近的研究提出的假设，以及我们使用新方法探测染色质的能力从历史上看，我们在精确的蛋白质相互作用方面做出了重大贡献。了解染色质结构域的靶向和传播，目前我们正在探索染色质因子为特定细胞类型的关键调控决策调整基因的能力。目前的研究重点是多梳族（PcG）蛋白，并且由于该蛋白的高度保守性我们在果蝇胚胎和人类胚胎干细胞之间轻松移动的关键调节系统。正在开发一种模型，其中关键调控基因在发育早期普遍“准备就绪” 通过占据多梳抑制复合物 1 (PRC1) 的复合蛋白复合物和这些“二价”蛋白质复合物可能会分解为完全激活或抑制，取决于细胞类型特异性表达、结合和转录功能我们推测转录因子可能相对混杂地结合，但仍然执行。精确的监管决策，当它们影响这些地方的局部乙酰化/脱乙酰化状态时我们的推测模型基于 PRC1 的强有力的蛋白质组学证据。与经典共激活剂 dBRD4 和 dMOZ/MORF 强烈相互作用，在染色质上捕获果蝇的胚胎发生，以及通过 CBX7、RING2（PRC1 的亚基）的类似共占用，和 BRD1（MOZ/MORF 的一个亚基）在人类胚胎干细胞中的应用从机械层面理解染色质转变和转录编程的尖端。这些研究还与我们对异常染色质复合物的分子解剖相协同导致人类癌症。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cell state-dependent chromatin targeting in NUT carcinoma.

NUT 癌中细胞状态依赖性染色质靶向。

DOI：
10.1093/genetics/iyad083
发表时间：
2023
期刊：
Genetics
影响因子：
3.3
作者：
Alekseyenko,ArtyomA;Zee,BarryM;Dhoondia,Zuzer;Kang,Hyuckjoon;Makofske,JessicaL;Kuroda,MitziI
通讯作者：
Kuroda,MitziI

Variant Polycomb complexes in Drosophila consistent with ancient functional diversity.