Comparative and functional analysis of conservation and rearrangement of topologically associating domains across mammals.
哺乳动物拓扑关联域的保护和重排的比较和功能分析。
基本信息
- 批准号:10189682
- 负责人:
- 金额:$ 71.4万
- 依托单位:
- 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:2018-09-14 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:ATAC-seqAffectBiologicalBiological AssayCCCTC-binding factorCRISPR/Cas technologyCSPG6 geneCell LineChIP-seqChromatinChromatin Conformation Capture and SequencingChromatin StructureChromosomal RearrangementChromosomesClinicalCongenital DisordersDNADNA Sequence RearrangementDataDeltastabDiseaseEnhancersEpigenetic ProcessEventEvolutionGene ActivationGene ExpressionGene Expression RegulationGenesGeneticGenetic DiseasesGenetic VariationGenomeGenomic DNAGenomicsHi-CHumanHylobates GenusIndividualKaryotypeKnowledgeLeadLightMalignant NeoplasmsMammalsMapsMissionModelingMolecular ConformationMusMutationOutcomePathologyPhenotypePongidaePortraitsPositioning AttributePublic HealthResearchResolutionResourcesRoleSourceStructureSyntenyTOP2B geneTestingTissue-Specific Gene ExpressionTreesUnited States National Institutes of HealthVariantcomparativecomparative genomicsdifferential expressionexperiencefunctional genomicsfunctional outcomesgenome editinggenome-widehuman diseasenovelpreventpromoterstructural genomicstranscriptome sequencing
项目摘要
PROJECT SUMMARY
Chromosomal rearrangements are a great source of inter- and intra-specific genetic variation and are major
contributors to human disease. Although position of rearrangement breakpoints can now be mapped at high
resolution, interpreting the evolutionary or clinical implications of these events remains challenging. Depending
on where they occur, rearrangements can disrupt the organization of genomic functional compartments, known
as topologically associating domains (TADs). Within TADs, nearby loci (i.e. promoters and enhancers) interact
frequently with each other, while interactions with loci outside TADs are prevented by TAD boundaries.
Disruption of TAD boundaries can result in ectopic genes regulation, aberrant phenotypes, and genetic
disorders. The functional outcomes of chromosomal rearrangements, therefore, can only be fully understood
when studied in the context of genome topology. To shed light on some of the evolutionary implications of
genome reorganization, we recently studied the gibbon genome, which has experienced rapid and recent
karyotype evolution with respect to human and the other apes. In the gibbon genome, we observed that TADs
remained genetically and epigenetically intact (genomic false-shuffle), because evolutionary breakpoints
overlapped almost exclusively with TAD boundaries. Comparison with human and other mammals shows that
these TAD boundaries are evolutionary conserved, indicating that TAD boundary establishment predated, and
may have even contributed to, occurrence of evolutionary breakage. Motivated by our preliminary findings in
gibbon, we propose to use a broad comparative and functional approach to assay multiple species with
naturally highly rearranged genomes across the Boreoeutheria tree, and characterize the genetic context,
epigenetic state, and evolutionary conservation of their TAD boundaries. We will determine if the false shuffle
is a recurring mechanism of genome evolution and we will identify chromatin states associated with
evolutionary fragility, as these regions and states could be relevant to human disease (Aim 1). Additionally, we
will determine the level of conservation for TAD boundaries across different clades. Overall, the combination of
these annotations will be a valuable resource to aid the interpretation of clinically and/or evolutionarily relevant
rearrangements. We will then use an evolutionary-motivated approach to delete a subset of highly conserved
and clade-specific TAD boundaries using CRISPR/Cas9 in cell lines and mouse, to assess the functional
consequences of their deletion on DNA interaction, chromatin state, and gene expression (Aim 2). Finally, by
analyzing differential gene expression and chromatin conformation between closely related species with
structurally different genomes, we will evaluate the extent to which chromosomal rearrangements can alter
short- and long-range functional interaction and contribute to differential gene expression (Aim 3). Overall, this
study will elucidate the epigenetics changes associated with evolutionary genome reorganization and will help
elucidating mechanisms by which genome rearrangement can lead to pathology.
项目概要
染色体重排是种间和种内遗传变异的重要来源,并且是重要的
人类疾病的贡献者。尽管现在可以将重排断点的位置映射到高位
分辨率,解释这些事件的进化或临床影响仍然具有挑战性。取决于
在发生的地方,重排会破坏基因组功能区室的组织,已知
作为拓扑关联域(TAD)。在 TAD 内,附近的基因座(即启动子和增强子)相互作用
彼此频繁地相互作用,而与 TAD 之外的基因座的相互作用则被 TAD 边界阻止。
TAD 边界的破坏可能导致异位基因调节、异常表型和遗传
失调。因此,染色体重排的功能结果只能被充分理解
当在基因组拓扑的背景下进行研究时。阐明某些进化意义
基因组重组,我们最近研究了长臂猿基因组,它经历了快速和最近的
人类和其他猿类的核型进化。在长臂猿基因组中,我们观察到 TAD
保持遗传和表观遗传完整(基因组假洗牌),因为进化断点
几乎完全与 TAD 边界重叠。与人类和其他哺乳动物的比较表明
这些 TAD 边界是进化保守的,表明 TAD 边界的建立早于
甚至可能导致进化断裂的发生。受到我们的初步调查结果的启发
长臂猿,我们建议使用广泛的比较和功能方法来测定多个物种
在整个 Boreoeutheria 树上自然地高度重排基因组,并表征遗传背景,
表观遗传状态及其 TAD 边界的进化保守性。我们将判断是否为虚假洗牌
是基因组进化的一种重复机制,我们将识别与相关的染色质状态
进化脆弱性,因为这些区域和状态可能与人类疾病相关(目标 1)。此外,我们
将确定跨不同进化枝的 TAD 边界的保护水平。总体而言,组合
这些注释将是帮助解释临床和/或进化相关的宝贵资源
重新安排。然后,我们将使用进化驱动的方法来删除高度保守的子集
在细胞系和小鼠中使用 CRISPR/Cas9 确定进化枝特异性 TAD 边界,以评估功能
它们的缺失对 DNA 相互作用、染色质状态和基因表达的影响(目标 2)。最后,由
分析密切相关物种之间的差异基因表达和染色质构象
结构不同的基因组,我们将评估染色体重排可以改变的程度
短程和长程功能相互作用并有助于差异基因表达(目标 3)。总体而言,这
研究将阐明与进化基因组重组相关的表观遗传学变化,并将有助于
阐明基因组重排导致病理的机制。
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)
Asymmetron: a toolkit for the identification of strand asymmetry patterns in biological sequences.
Asymmetron:用于识别生物序列中链不对称模式的工具包。
- DOI:
- 发表时间:2021-01-11
- 期刊:
- 影响因子:14.9
- 作者:Georgakopoulos;Mouratidis, Ioannis;Parada, Guillermo E;Matharu, Navneet;Hemberg, Martin;Ahituv, Nadav
- 通讯作者:Ahituv, Nadav
Comparative Analyses of Gibbon Centromeres Reveal Dynamic Genus-Specific Shifts in Repeat Composition.
长臂猿着丝粒的比较分析揭示了重复组成的动态属特异性变化。
- DOI:
- 发表时间:2021
- 期刊:
- 影响因子:10.7
- 作者:Hartley, Gabrielle A;Okhovat, Mariam;O'Neill, Rachel J;Carbone, Lucia
- 通讯作者:Carbone, Lucia
Absent from DNA and protein: genomic characterization of nullomers and nullpeptides across functional categories and evolution.
DNA 和蛋白质中不存在:跨功能类别和进化的 nullomer 和 nullpeptides 的基因组表征。
- DOI:
- 发表时间:2021-08-25
- 期刊:
- 影响因子:12.3
- 作者:Georgakopoulos;Yizhar;Mouratidis, Ioannis;Hemberg, Martin;Ahituv, Nadav
- 通讯作者:Ahituv, Nadav
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Lucia Carbone其他文献
Lucia Carbone的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Lucia Carbone', 18)}}的其他基金
Comparative Analysis of Aneuploidy and Cellular Fragmentation Dynamics in Mammalian Embryos
哺乳动物胚胎非整倍性和细胞破碎动力学的比较分析
- 批准号:
10366610 - 财政年份:2022
- 资助金额:
$ 71.4万 - 项目类别:
Comparative Analysis of Aneuploidy and Cellular Fragmentation Dynamics in Mammalian Embryos
哺乳动物胚胎非整倍性和细胞破碎动力学的比较分析
- 批准号:
10596997 - 财政年份:2022
- 资助金额:
$ 71.4万 - 项目类别:
INVESTIGATING THE ASSOCIATION BETWEEN HYPOMETHYLATION OF TRANSPOSABLE ELEMENTS
研究转座元件低甲基化之间的关联
- 批准号:
8357854 - 财政年份:2011
- 资助金额:
$ 71.4万 - 项目类别:
相似国自然基金
马铃薯分泌物靶向调控土壤微生物组装配影响疮痂病发生的生态机制研究
- 批准号:42377309
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
基于lncRNA NONHSAT042241/hnRNP D/β-catenin轴探讨雷公藤衍生物(LLDT-8)对类风湿关节炎滑膜成纤维细胞功能影响及机制研究
- 批准号:82304988
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
氢的异裂活化与氢负物种迁移对生物质C-O键活化裂解的影响机制
- 批准号:22372029
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
高寒草甸灌丛化过程中根系分泌物对土壤碳氮转化的影响及微生物机制
- 批准号:32371649
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
氮沉降影响南亚热带森林土壤颗粒和矿物结合态碳库蓄存的微生物学机制
- 批准号:32301366
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
The Role of Chromosome Y in Human Microglia and Neurodevelopment
Y 染色体在人类小胶质细胞和神经发育中的作用
- 批准号:
10680304 - 财政年份:2023
- 资助金额:
$ 71.4万 - 项目类别:
Characterizing HIV-1 reservoirs in the central nervous system
中枢神经系统中 HIV-1 储存库的特征
- 批准号:
10772268 - 财政年份:2023
- 资助金额:
$ 71.4万 - 项目类别:
Using cellular co-biosis and age programmable mice to derive a global interaction map of aging hallmarks
使用细胞共生和年龄可编程小鼠来得出衰老标志的全局相互作用图
- 批准号:
10721454 - 财政年份:2023
- 资助金额:
$ 71.4万 - 项目类别:
Elucidating the epigenetic regulation of extracellular matrix and virus-induced fibroblast activation
阐明细胞外基质和病毒诱导的成纤维细胞活化的表观遗传调控
- 批准号:
10572863 - 财政年份:2023
- 资助金额:
$ 71.4万 - 项目类别:
Gene regulatory networks in early lung epithelial cell fate decisions
早期肺上皮细胞命运决定中的基因调控网络
- 批准号:
10587615 - 财政年份:2023
- 资助金额:
$ 71.4万 - 项目类别: