Mechanism of chromatin accessibility, 3D chromosome organization, and their functions in gene regulation
染色质可及性机制、3D 染色体组织及其在基因调控中的功能
基本信息
- 批准号:10887047
- 负责人:
- 金额:$ 1.77万
- 依托单位:
- 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:2021-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAllelesBindingBinding SitesBiological AssayCellsChromatinChromatin StructureChromosome StructuresChromosomesDiseaseDrosophila genusEquipmentEventFoundationsFundingGene ClusterGene ExpressionGene Expression RegulationGenesGeneticGenetic ScreeningGenomeGoalsGrantHealthHumanHuman Cell LineImageInvadedKineticsLinkLiquid substanceMalignant NeoplasmsMediatingMethodsNational Institute of General Medical SciencesNucleosomesOligonucleotidesPhasePlayPluripotent Stem CellsResearchRoleSaccharomycetalesSamplingSystemTestingUpdateYeastschromosome conformation capturecofactordevelopmental diseaseinnovationinsightnovelprograms
项目摘要
Project Summary/Abstract
The overall theme of my research program is to understand the formation mechanism of chromatin structure
and its role in gene regulation. We plan to address this problem at two different levels: 1) at the
chromatin / nucleosome level, we will identify pioneer factors (PFs) and investigate the mechanism underlying
nucleosome displacement and chromatin opening, and 2) at the chromosome level, we will study the
mechanism of gene regulation by high-order 3D chromosome organization. In the past five years,
supported by two NIGMS R01 grants, we have made significant progress in both directions. New
observations and insights we gained from these studies, as well as several novel methods we developed,
form the foundation of this proposal.
Theme1: Pioneer factors (PFs) can invade nucleosome and increase chromatin accessibility near their binding
sites and therefore play critical roles in gene regulation. Mis-regulation of PFs is highly linked to cancer
and developmental disease. Despite their essential functions, only a handful of PFs have been identified
and the mechanism underlying the pioneer activity is unclear. The long term goal of this theme is to
systematically characterize PFs and their pioneer activities in health and disease cells, and to develop a full
understanding of the mechanism of these activities. In our recent PF studies, we have innovated an
Integrated Synthetic Oligo (ISO) assay to investigate PF function in a high-throughput manner. In the next five
years, we plan to 1) adapt the ISO assay into human cell lines and pluripotent stem cells to dissect the genetic
rules underlying PF binding and nucleosome displacement, and 2) further our understanding of the pioneering
activity by investigating the co-factors of PFs, the sequence of events during nucleosome displacement, and
the kinetic rates of these events.
Theme2: Imaging and 3C-based methods have revealed 3D chromosome organization with extensive
long-distance chromosomal interactions. The long-term goal of this theme is to understand the formation
mechanism of these high-order chromosome structures and their roles in gene regulation. Our recent studies
show that long-distance chromosomal interactions contribute to gene regulation in yeast. More specifically,
some allelic or co-regulated genes cluster in the 3D space, and such clustering is correlated with higher gene
activities. The former case is analogous to the “transvection” phenomenon in Drosophila. These novel
observations revealed a new layer of gene regulation in yeast and opened the opportunity of using the
powerful genetic system to investigate the 3D genome function. Currently we have little understanding of what
mediates the cluster formation and how the clusters enhance gene expression. In the next five years, we plan
to 1) use an unbiased genetic screen to identify factors that negatively regulate transvection, and investigate
the underlying mechanism, and 2) test the hypothesis that some activators condense though liquid-liquid
phase separation, leading to the clustering of co-regulated genes and enhanced expression.
项目总结/摘要
我的研究计划的总体主题是了解染色质结构的形成机制
及其在基因调控中的作用。我们计划在两个不同层面解决这个问题:1)在
染色质/核小体水平,我们将确定先锋因子(PFs),并研究其机制
核小体移位和染色质开放,2)在染色体水平上,我们将研究
通过高阶3D染色体组织的基因调控机制。在过去的五年里,
在两个NIGMS R 01赠款的支持下,我们在两个方向上都取得了重大进展。新
我们从这些研究中获得的观察和见解,以及我们开发的几种新方法,
这是这项提议的基础。
主题1:先锋因子(Pioneer factors,PFs)可以侵入核小体,并增加其结合附近的染色质可及性
位点,因此在基因调控中发挥关键作用。PFs的错误调节与癌症高度相关
和发育性疾病。尽管它们具有重要的功能,但只有少数几个PF被确定
而这种先驱活动背后的机制尚不清楚。本主题的长期目标是
系统地描述PF及其在健康和疾病细胞中的先驱活动,并开发一个完整的
了解这些活动的机制。在我们最近的PF研究中,我们创新了一种
综合合成寡核苷酸(ISO)测定,以高通量方式研究PF功能。未来五
我们计划1)将ISO检测法应用于人类细胞系和多能干细胞,以剖析遗传学上的差异。
PF结合和核小体置换的基本规则,以及2)进一步理解了
通过研究PF的辅因子,核小体移位过程中的事件顺序,
这些事件的动力学速率。
主题2:成像和基于3C的方法已经揭示了具有广泛的三维染色体组织
长距离染色体相互作用。本主题的长期目标是了解
这些高阶染色体结构的机制及其在基因调控中的作用。我们最近的研究
显示长距离染色体相互作用有助于酵母中基因调控。更具体地说,
一些等位基因或共调控基因在3D空间中聚类,并且这种聚类与更高的基因相关,
活动前一种情况类似于果蝇中的“transvection”现象。这些新颖
观察揭示了酵母中新的基因调控层,并打开了使用
强大的遗传系统来研究3D基因组功能。目前,我们还不太了解
介导簇的形成以及簇如何增强基因表达。未来五年,我们计划
1)使用无偏倚的遗传筛选来鉴定负调节transvection的因子,并研究
潜在的机制,和2)测试的假设,一些活化剂冷凝,通过液-液
相分离,导致共调节基因的聚集和增强的表达。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Predicting nucleosome positioning using statistical equilibrium models in budding yeast.
- DOI:10.1016/j.xpro.2022.101926
- 发表时间:2023-03-17
- 期刊:
- 影响因子:0
- 作者:Kharerin, Hungyo;Bai, Lu
- 通讯作者:Bai, Lu
Partitioned usage of chromatin remodelers by nucleosome-displacing factors.
- DOI:10.1016/j.celrep.2022.111250
- 发表时间:2022-08-23
- 期刊:
- 影响因子:8.8
- 作者:Chen, Hengye;Kharerin, Hungyo;Dhasarathy, Archana;Kladde, Michael;Bai, Lu
- 通讯作者:Bai, Lu
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{{ truncateString('Lu Bai', 18)}}的其他基金
Mechanism of chromatin accessibility, 3D chromosome organization, and their functions in gene regulation
染色质可及性机制、3D 染色体组织及其在基因调控中的功能
- 批准号:
10536599 - 财政年份:2021
- 资助金额:
$ 1.77万 - 项目类别:
Mechanism of chromatin accessibility, 3D chromosome organization, and their functions in gene regulation
染色质可及性机制、3D 染色体组织及其在基因调控中的功能
- 批准号:
10322650 - 财政年份:2021
- 资助金额:
$ 1.77万 - 项目类别:
Mechanism of Chromatin Accessibility, 3D Chromosome Organization, and Their Functions in Gene Regulation
染色质可及性机制、3D 染色体组织及其在基因调控中的功能
- 批准号:
10594324 - 财政年份:2021
- 资助金额:
$ 1.77万 - 项目类别:
Gene Regulation from Long-Distance Chromosomal Interactions in Yeast
酵母中长距离染色体相互作用的基因调控
- 批准号:
9923700 - 财政年份:2016
- 资助金额:
$ 1.77万 - 项目类别:
Gene Regulation from Long-Distance Chromosomal Interactions in Yeast
酵母中长距离染色体相互作用的基因调控
- 批准号:
9270572 - 财政年份:2016
- 资助金额:
$ 1.77万 - 项目类别:
Gene Regulation from Long-Distance Chromosomal Interactions in Yeast
酵母中长距离染色体相互作用的基因调控
- 批准号:
9474142 - 财政年份:2016
- 资助金额:
$ 1.77万 - 项目类别:
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