Protein Regulators of 3D Genome Architecture: Dynamics, Mechanism and Function

3D 基因组结构的蛋白质调节因子：动力学、机制和功能

• 批准号: 2036037
• 负责人: Anders Hansen
• 金额: $ 76万
• 依托单位: Massachusetts Institute of Technology
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2036037&HistoricalAwards=false
• 关键词: Protein; Regulators; 3D; Genome; Architecture

The research project will contribute to our understanding of 3D genome folding. Proper regulation of gene expression is essential in all biological organisms. In mammals, most genes are regulated by distal enhancers that can be located far away from their target genes on the linear genome. Perhaps for this reason, mammalian genomes are folded into 3D domains that ensure enhancers interact with the appropriate genes through space. This research will provide key insights into an understudied potential regulator of 3D genome domains. The project will create interdisciplinary training opportunities for a graduate student and a post-doctoral associate, supporting their development as scientists in academia, biomedical industry and/or related careers. Additional broader impact will be achieved through integration of the imaging aspects of the project with an undergraduate course at MIT (20.309), summer research opportunities for undergraduates from underrepresented groups in STEM disciplines and through outreach activities. CTCF is the best-known insulator between enhancers and promoters in mammalian cells. CTCF, together with the cohesin complex, fold the genome into chromatin loops and loop domains. However, not all loops have CTCF at their anchors, and since CTCF is expressed in all cell types, it is currently difficult to explain why loops differ between cell types. Moreover, several studies have provided evidence that other DNA-binding proteins are strongly enriched at loop anchors. The research will study such a candidate looping factor, ZNF143, in detail. Acute depletion followed by Micro-C will reveal its role in 3D genome organization and looping. Live-cell and super-resolution microscopy will reveal its dynamics, target-search mechanism, residence time, and provide quantitative constraints on 3D genome models. Taken together, the research will expand knowledge of critical genome organizing factors beyond CTCF.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该研究项目将有助于我们对 3D 基因组折叠的理解。基因表达的正确调节对于所有生物体都是至关重要的。在哺乳动物中，大多数基因受到远端增强子的调节，这些增强子可以位于远离线性基因组上的靶基因的位置。也许出于这个原因，哺乳动物基因组被折叠成 3D 结构域，以确保增强子通过空间与适当的基因相互作用。这项研究将为研究 3D 基因组域的潜在调节因子提供重要见解。该项目将为研究生和博士后创造跨学科培训机会，支持他们作为学术界、生物医学行业和/或相关职业的科学家的发展。通过将该项目的成像方面与麻省理工学院的本科课程 (20.309) 相结合、为 STEM 学科中代表性不足的群体的本科生提供暑期研究机会以及通过外展活动，将实现更广泛的影响。 CTCF 是哺乳动物细胞中增强子和启动子之间最著名的绝缘体。 CTCF 与粘连蛋白复合物一起将基因组折叠成染色质环和环结构域。然而，并非所有环的锚定点都具有 CTCF，并且由于 CTCF 在所有细胞类型中表达，因此目前很难解释为什么环在细胞类型之间存在差异。此外，多项研究提供的证据表明，其他 DNA 结合蛋白在环锚点处高度富集。该研究将详细研究这样一个候选循环因子 ZNF143。 Micro-C 的急性消耗将揭示其在 3D 基因组组织和循环中的作用。活细胞和超分辨率显微镜将揭示其动力学、目标搜索机制、停留时间，并提供 3D 基因组模型的定量约束。总而言之，该研究将扩展 CTCF 之外的关键基因组组织因素的知识。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Reeling it in: how DNA topology drives loop extrusion by condensin

卷入：DNA 拓扑结构如何通过凝缩蛋白驱动环挤出

• DOI: 10.1038/s41594-022-00805-8
• 发表时间: 2022-07
• 期刊: Nature Structural & Molecular Biology
• 影响因子: 16.8
• 作者: Narducci, Domenic N.;Hansen, Anders S.
• 通讯作者: Hansen, Anders S.

The macro and micro of chromosome conformation capture

染色体构象捕获的宏观和微观

• DOI: 10.1002/wdev.395
• 发表时间: 2021-11
• 期刊: Wiley Interdisciplinary Reviews. Developmental Biology
• 作者: Goel VY;Hansen AS
• 通讯作者: Hansen AS

Dynamics of CTCF- and cohesin-mediated chromatin looping revealed by live-cell imaging

活细胞成像揭示 CTCF 和粘连蛋白介导的染色质环的动态

• DOI: 10.1126/science.abn6583
• 发表时间: 2022-04
• 期刊: Science
• 影响因子: 56.9
• 作者: Gabriele, Michele;Brandão, Hugo B.;Grosse;Jha, Asmita;Dailey, Gina M.;Cattoglio, Claudia;Hsieh, Tsung;Mirny, Leonid;Zechner, Christoph;Hansen, Anders S.
• 通讯作者: Hansen, Anders S.

Right on target: Chromatin jets arise from targeted cohesin loading in wild-type cells

正中目标：染色质喷射是由野生型细胞中的定向粘连蛋白负载产生的

• DOI: 10.1016/j.molcel.2022.09.027
• 发表时间: 2022-10-20
• 期刊: Molecular Cell
• 影响因子: 16
• 作者: Drayton, Jamie A.;Hansen, Anders S.
• 通讯作者: Hansen, Anders S.