Developmental and evolutionary dynamics of tissue-specific mammalian enhancers.
组织特异性哺乳动物增强子的发育和进化动力学。
基本信息
- 批准号:8732476
- 负责人:
- 金额:$ 0.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-08-01 至 2014-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAddressAdultAntibodiesBerylliumBindingBinding SitesBiologicalBiological AssayBiological ModelsBiological ProcessBiomedical ResearchBrainCatalogingCatalogsComputer AnalysisCoupledDNADNA SequenceDataData SetDevelopmentDiseaseElementsEmbryoEmbryonic DevelopmentEmbryonic HeartEnhancersEvolutionExhibitsFunctional RNAGene ExpressionGene Expression RegulationGenetic TranscriptionGenomicsGoalsHeartHistonesHumanLaboratoriesLiverMapsMethodsMolecular EvolutionMusPathway interactionsPatternPlayPregnancyProsencephalonRegulator GenesRegulatory ElementRoleSamplingSequence AnalysisSeriesSpecificityStagingTechniquesTestingTimeTissue SampleTissuesTransgenic MiceValidationWorkbiomedical resourcebody systembrain tissuechromatin immunoprecipitationcomparative genomicsdesignepigenomicsgenome wide association studygenome-widehuman diseasein vivoinsightinterestmammalian genomemouse developmentnovelpostnatalprenatalpressurepublic health relevanceresearch studytranscription factor
项目摘要
DESCRIPTION (provided by applicant): Enhancers are remotely acting non-coding DNA elements that regulate the tissue-specific and developmental expression of genes. Enhancers are thought to be a major driver of vertebrate evolution, and there is increasing evidence that they play important roles in human disorders. Two complementary, powerful approaches to identify tissue-specific enhancers at a genomic scale are the use of extreme evolutionary conservation of non-coding sequences and, more recently, the mapping of enhancer-associated epigenomic marks by chromatin immunoprecipitation coupled to sequencing (ChIP-seq). Surprisingly, ChIP-seq studies of different embryonic mouse tissues revealed that enhancers active in some tissues, such as the embryonic brain, are under severe evolutionary sequence constraint whereas enhancers active in other tissues, such as the embryonic heart, are only mildly constrained. These results raise the possibility that patterns of evolutionary constraint generally differ between enhancers active in different tissues. Alternatively, it is possible that he degree of enhancer constraint in a specific tissue changes during development, and those differences in timing of these changes account for the observed differences in enhancer conservation between tissues. I propose to examine these two possibilities through a combination of experimental and computational approaches aimed at the identification and sequence analysis of genome-wide sets of enhancers active in the mouse from mid-gestation through adulthood in three tissues with different developmental trajectories. The specific aims include: 1) Identify active enhancers through ChIP-seq performed on brain, liver and heart tissue sampled across eight time points of pre- and postnatal mouse development; 2) Classify the degree of evolutionary constraint associated with active enhancers in the three tissues at all time points sampled; 3) Validate changes in activity through development in vivo using mouse transgenic enhancer assays for a selected set of enhancers. This study is expected to elucidate the evolutionary constraint signatures of enhancers active in different tissues at the same developmental time point, as well as possible constraint differences between enhancers active in the same tissue at different developmental stages. Importantly, the results will help to explain
why gene expression in evolutionarily old organ systems like the heart appears to be under the control of poorly conserved enhancers. This is expected to have direct implications for our understanding of the role of enhancers in vertebrate evolution. In addition to enabling fundamental evolutionary insights, the data sets generated through this proposal will also provide a valuable resource for biomedical studies, since they are expected to reveal large numbers of currently unrecognized enhancers with transient developmental activities in three tissues of major biomedical interest.
描述(申请人提供):增强子是远程作用的非编码DNA元件,调节基因的组织特异性和发育表达。增强剂被认为是脊椎动物进化的主要驱动力,越来越多的证据表明,它们在人类疾病中发挥着重要作用。在基因组水平上识别组织特异性增强子的两种互补的、强大的方法是使用非编码序列的极端进化保守,以及最近通过染色质免疫沉淀与测序相结合的增强子相关表观基因组标记的映射(CHIP-SEQ)。令人惊讶的是,对不同胚胎小鼠组织的芯片序列研究显示,在某些组织中活跃的增强子,如胚胎大脑,受到严格的进化序列限制,而在其他组织中活跃的增强子,如胚胎心脏,只受到轻微的限制。这些结果提出了这样一种可能性,即不同组织中活性的增强剂之间的进化限制模式通常不同。或者,可能是特定组织中增强子的限制程度在发育过程中发生了变化,这些变化的时间上的差异解释了观察到的不同组织之间增强子保守性的差异。我建议通过实验和计算相结合的方法来研究这两种可能性,这些方法旨在识别和分析小鼠从妊娠中期到成年期三个不同发育轨迹的组织中活跃的基因组范围的增强子集。具体目标包括:1)通过对小鼠出生前和出生后八个时间点的大脑、肝脏和心脏组织进行芯片序列分析来确定活性增强剂;2)对所有采样时间点的三种组织中与活性增强剂相关的进化约束程度进行分类;3)通过对选定的一组增强剂进行小鼠转基因增强子分析,验证通过体内发育过程中活性的变化。这项研究有望阐明在同一发育时间点不同组织中活性的增强子的进化约束特征,以及同一组织中不同发育阶段活性的增强子之间可能存在的约束差异。重要的是,研究结果将有助于解释
为什么像心脏这样的进化古老的器官系统中的基因表达似乎受到保守程度不高的增强子的控制。这有望对我们理解增强剂在脊椎动物进化中的作用产生直接的影响。除了实现基本的进化洞察外,通过这一提议产生的数据集也将为生物医学研究提供宝贵的资源,因为它们有望揭示大量目前未被识别的增强剂,它们在三个主要生物医学感兴趣的组织中具有短暂的发育活动。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
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 }}
Alexander Nord其他文献
Alexander Nord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('Alexander Nord', 18)}}的其他基金
Single cell RNA profiles of opioid dependence
阿片类药物依赖的单细胞 RNA 谱
- 批准号:
10728129 - 财政年份:2023
- 资助金额:
$ 0.79万 - 项目类别:
Testing naturally-occurring mutations for impact on brain enhancer function
测试自然发生的突变对大脑增强功能的影响
- 批准号:
10207123 - 财政年份:2021
- 资助金额:
$ 0.79万 - 项目类别:
Testing naturally-occurring mutations for impact on brain enhancer function
测试自然发生的突变对大脑增强功能的影响
- 批准号:
10357952 - 财政年份:2021
- 资助金额:
$ 0.79万 - 项目类别:
Causal biology of Chd8 haploinsufficiency in complex brain disorders
复杂脑部疾病中 Chd8 单倍体不足的因果生物学
- 批准号:
9974570 - 财政年份:2019
- 资助金额:
$ 0.79万 - 项目类别:
Causal biology of Chd8 haploinsufficiency in complex brain disorders
复杂脑部疾病中 Chd8 单倍体不足的因果生物学
- 批准号:
9811334 - 财政年份:2019
- 资助金额:
$ 0.79万 - 项目类别:
Causal biology of Chd8 haploinsufficiency in complex brain disorders
复杂脑部疾病中 Chd8 单倍体不足的因果生物学
- 批准号:
10395475 - 财政年份:2019
- 资助金额:
$ 0.79万 - 项目类别:
Causal biology of Chd8 haploinsufficiency in complex brain disorders
复杂脑部疾病中 Chd8 单倍体不足的因果生物学
- 批准号:
10621144 - 财政年份:2019
- 资助金额:
$ 0.79万 - 项目类别:
Functional elucidation of the sequence-encoded regulatory activity of enhancers in vivo in the brain
大脑体内增强子序列编码调节活性的功能阐明
- 批准号:
10330886 - 财政年份:2016
- 资助金额:
$ 0.79万 - 项目类别:
Functional elucidation of the sequence-encoded regulatory activity of enhancers in vivo in the brain
大脑体内增强子序列编码调节活性的功能阐明
- 批准号:
10543480 - 财政年份:2016
- 资助金额:
$ 0.79万 - 项目类别:
Functional Elucidation of the Sequence-Encoded Regulatory Activity of Enhancers in Vivo in the Brain
大脑体内增强子序列编码调节活性的功能阐明
- 批准号:
9335929 - 财政年份:2016
- 资助金额:
$ 0.79万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 0.79万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 0.79万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 0.79万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 0.79万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 0.79万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 0.79万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 0.79万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 0.79万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 0.79万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 0.79万 - 项目类别:
Research Grant