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Investigating the role of genome folding in transcriptional regulation

研究基因组折叠在转录调控中的作用

基本信息

批准号：
10641807
负责人：
Elphege-Pierre Julien Nora
金额：
$ 40.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-09 至 2026-06-30
项目状态：
未结题

项目摘要

Project Summary During transcription, enhancers need to contact gene promoters across large chromosome domains. Chromosome folding can assist enhancer-promoter communication by bringing them close together inside the nucleus. Mutations that alter genome folding underlie many human diseases, including developmental disorders and some cancers. Yet, even after decades of research, we do not understand the causal links between chromatin architecture and transcription regulation. Specifically, we do not understand why DNA looping can correlate positively, negatively, or sometimes not at all with gene activity. To move beyond correlation to causation, we need to better understand the molecular processes that couple genome folding and gene regulation. The cohesin complex has emerged as a key player in DNA looping, because it can hold two chromatin fibers together and extrude DNA loops as it translocates on DNA. Cohesin is loaded on chromatin by its co-factor NIPBL. Cohesin then translocates until it is blocked at binding sites for the CTCF transcription factor. We recently developed tools that allow controlling various aspects of cohesin loop extrusion by manipulating NIPBL and CTCF in mouse embryonic stem cells. These tools provide a novel approach to investigate the relationship between loop extrusion by cohesin and transcription. In this proposed study, we will determine how transcription and loop extrusion are molecularly coupled and elucidate the mechanisms that explain why only some genes rely on loop extrusion to function. We will also address how cohesin loop extrusion contributes to the functions of CTCF during cell differentiation. In addition, we will identify novel pathways that regulate enhancer-promoter communication by modulating loop extrusion. To achieve these goals, we will combine gene editing, epigenomic assays, biochemical assays and novel epigenome engineering modalities with high-throughput reporter assays in mouse embryonic stem cells and their differentiated derivatives. These investigations will substantially deepen our understanding of how genome folding by cohesin proteins influences gene transcription. Completion of this project will open new avenues to explore how these processes go awry in disease, a question our group is interested to investigate in the future.

项目总结

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Emerging questions in transcriptional regulation.

转录调控中新出现的问题。

DOI：
10.1016/j.cels.2023.03.005
发表时间：
2023
期刊：
Cell systems
影响因子：
9.3
作者：
Nora,ElphègeP;Aerts,Stein;Wittkopp,PatriciaJ;Bussemaker,HarmenJ;Bulyk,Martha;Sinha,Saurabh;Zeitlinger,Julia;Crocker,Justin;FuxmanBass,JuanIgnacio
通讯作者：
FuxmanBass,JuanIgnacio

Transcription and topoisomerases bring new twists to DNA loop extrusion by cohesin.

转录和拓扑异构酶为粘连蛋白的 DNA 环挤出带来了新的变化。

DOI：
10.1016/j.molcel.2021.07.012
发表时间：
2021
期刊：
Molecular cell
影响因子：
16
作者：
Shah,Rini;Nora,ElphègeP
通讯作者：
Nora,ElphègeP

Embryogenesis without CTCF in flies and vertebrates.

果蝇和脊椎动物无 CTCF 的胚胎发生。

DOI：
10.1038/s41594-021-00662-x
发表时间：
2021
期刊：
Nature structural & molecular biology
影响因子：
16.8
作者：
Fudenberg,Geoffrey;Nora,ElphègeP
通讯作者：
Nora,ElphègeP

CTCF is a barrier for 2C-like reprogramming.

DOI：
10.1038/s41467-021-25072-x
发表时间：
2021-08-11
期刊：
Nature communications
影响因子：
16.6
作者：
Olbrich T;Vega-Sendino M;Tillo D;Wu W;Zolnerowich N;Pavani R;Tran AD;Domingo CN;Franco M;Markiewicz-Potoczny M;Pegoraro G;FitzGerald PC;Kruhlak MJ;Lazzerini-Denchi E;Nora EP;Nussenzweig A;Ruiz S
通讯作者：
Ruiz S

Lesson of regulatory anatomy: Using integrated functional genomics to dissect the X-inactivation center.

调控解剖学课程：使用集成功能基因组学剖析 X 失活中心。