Pathogenic Alterations of the 3D Epigenetic Landscape in Dystrophin-Deficient Skeletal Muscles and Reversal by Dystrophin Re-Expression
肌营养不良蛋白缺陷骨骼肌 3D 表观遗传景观的致病性改变以及肌营养不良蛋白重新表达的逆转
基本信息
- 批准号:10631048
- 负责人:
- 金额:$ 65.3万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-08-01 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalATAC-seqAddressAffectArchitectureBindingBioinformaticsCellsCessation of lifeChIP-seqChildhoodChromatinChromatin StructureChronic DiseaseDataData AnalysesDimensionsDiseaseDisease ProgressionDuchenne muscular dystrophyDystrophinElementsEpigenetic ProcessEvaluationEventExhibitsExperimental ModelsFingerprintFundingGene ExpressionGene Expression ProfileGene Expression ProfilingGenesGenetic TranscriptionGenomeGenomic InstabilityGenomicsHi-CHumanKnowledgeLifeLogicModelingMusMuscleMuscle ContractionMuscle FibersMuscular DystrophiesMutationNuclearOutputPathogenesisPathogenicityPatientsPredispositionRecoveryRegulationSarcolemmaSkeletal MuscleStimulusTechnologyTherapeuticTranscription AlterationTransforming Growth Factor betaTreatment EfficacyUnited States National Institutes of HealthUntranslated RNAWheelchairsWild Type Mouseboyschromosome conformation capturedisease-causing mutationfollow-upfunctional genomicsgene therapygene therapy clinical trialgenome integritygenome-widehistone modificationhuman modelin vivoin vivo Modelinduced pluripotent stem cellinterestmdx mousemembrane skeletonmouse modelmutantprematurepromoterprotein complexresponserestorationskeletalskeletal muscle wastingtranscriptometranscriptome sequencingtreatment responsevirulence gene
项目摘要
PROJECT SUMMARY
Lack of dystrophin (dys) and disruption of the dys-associated protein complex (DAPC) at the membrane of
skeletal myofibers are widely recognized as the main cause of sarcolemma instability, leading to skeletal
muscle loss in patients affected by Duchenne Muscular Dystrophy (DMD). In addition to its structural function,
dys has been implicated in the regulation of additional downstream cellular events, including control of the
genome integrity and gene expression. Indeed, dys-deficient muscles exhibit altered profiles of histone
modifications, gene expression and non-coding RNA, as well as features of genomic instability and nuclear
abnormalities. Chromosome conformation capture (3C)-based studies have revealed that the genome is folded
into high-order chromatin interactions. Understanding the relationship between dys deficiency, dysregulated
gene expression and altered genome topology is of special interest for the complete understanding of DMD
pathogenesis and for the evaluation of the effective benefits of therapeutic approaches aimed at replacing dys
expression in DMD boys. This proposal addresses this question by exploiting state-of-the-art genome-wide
approaches (i.e. promoter capture-HiC, ChIP-seq, ATAC-seq and RNAseq) to detect perturbations of the
epigenetic landscape and transcriptome in DMD muscles, using two complementary experimental models –
patient iPSC-based in dish model of human DMD vivo and the mdx mouse model in vivo, by the following
Aims: Aim 1. To identify alterations in high-order chromatin interactions that regulate gene expression
in DMD muscles We will identify alterations of chromatin interactions between functional and structural
genomic elements, leading to pathogenic gene expression in human (hiPSC-derived skeletal muscles) and
mouse (mdx mice) models of DMD. Aim 2. Effect of µ-dys restoration on reversal of alterations in high-
order chromatin interactions that regulate gene expression in DMD muscles We will evaluate whether
restoration of dys expression by µ-dys reverses (partly or completely) the epigenetic and transcriptional
alterations of DMD muscles identified in Aim 1. Aim 3. Bioinformatic identification and analysis of
epigenetic and transcriptional alterations in DMD muscles We will perform an integrated bioinformatic
analysis of pcHi-C, RNA-seq, ATAC-seq and ChIP-seq data to identify DMD-associated pathogenic chromatin
interactions (DMD PCI) in DMD MuSCs and myofibers, and their susceptibility to µ-dys expression. Aim 4.
Contraction-induced alterations in high-order chromatin interactions at pathogenic loci in DMD
muscles and reversibility by dys restoration We will determine the effect of muscle contraction on PCI and
gene expression at loci of pathogenic genes, within the context of dys deficiency and upon µ-dys recovery.
Understanding whether dys deficiency causes epigenetic perturbations responsible for pathogenic
transcriptional output of DMD muscles, and whether they could be reversed by µ-dys expression, will invariably
extend our knowledge on DMD pathogenesis and on the therapeutic efficacy of µ-dys based gene therapies.
项目摘要
缺乏肌营养不良蛋白(dys)和破坏dys相关蛋白复合物(DAPC)在膜
骨骼肌纤维被广泛认为是肌膜不稳定的主要原因,导致骨骼肌损伤。
杜氏肌营养不良症(DMD)患者的肌肉损失。除了结构功能外,
dys参与调节其他下游细胞事件,包括控制细胞内的
基因组完整性和基因表达。确实,缺乏缺陷的肌肉表现出组蛋白的改变,
修饰,基因表达和非编码RNA,以及基因组不稳定性和核
异常基于染色体构象捕获(3C)的研究表明,基因组是折叠的,
转化为高级染色质相互作用。了解dys缺乏,失调
基因表达和改变的基因组拓扑结构对于全面了解DMD具有特殊意义
发病机制和评价旨在替代dys的治疗方法的有效益处
DMD男孩的表现。这项提案通过利用最先进的全基因组技术来解决这个问题。
方法(即启动子捕获-HiC,ChIP-seq,ATAC-seq和RNAseq)来检测微环境的扰动。
DMD肌肉的表观遗传景观和转录组,使用两个互补的实验模型-
基于患者iPSC的人DMD体内培养皿模型和mdx小鼠体内模型,
目标:目标1。鉴定调节基因表达的高级染色质相互作用的改变
在DMD肌肉中,我们将识别功能和结构之间的染色质相互作用的改变,
基因组元件,导致人类(hiPSC衍生的骨骼肌)中的致病基因表达,
DMD的小鼠(mdx小鼠)模型。目标二。微-dys修复对逆转高-
顺序染色质相互作用调节DMD肌肉中的基因表达我们将评估
通过µ-dys恢复dys表达逆转(部分或完全)表观遗传和转录
目的1中鉴定的DMD肌肉的改变。目标3.生物信息学鉴定与分析
DMD肌肉的表观遗传和转录改变我们将进行一个综合的生物信息学
分析pcHi-C、RNA-seq、ATAC-seq和ChIP-seq数据以鉴定DMD相关致病性染色质
研究DMD MuSC和肌纤维中的DMD PCI相互作用及其对µ-dys表达的易感性。目标4。
收缩诱导的DMD致病基因位点的高级染色质相互作用的改变
我们将确定肌肉收缩对PCI的影响,
在dys缺乏和µ-dys恢复的情况下,致病基因位点的基因表达。
了解dys缺乏是否会导致致病性
DMD肌肉的转录输出,以及它们是否可以被µ-dys表达逆转,将不可避免地
扩展我们对DMD发病机制和基于µ-dys的基因疗法的治疗效果的知识。
项目成果
期刊论文数量(30)
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 }}
Pier Lorenzo Puri其他文献
Nitric Oxide and Histone Acetylation—Shaping Craniofacial Development
- DOI:
10.1016/j.chembiol.2014.05.002 - 发表时间:
2014-05-22 - 期刊:
- 影响因子:
- 作者:
Libera Berghella;Pier Lorenzo Puri - 通讯作者:
Pier Lorenzo Puri
HDAC inhibitors as pharmacological treatment for Duchenne muscular dystrophy: a discovery journey from bench to patients
组蛋白去乙酰化酶抑制剂作为杜氏肌营养不良症的药物治疗方法:从实验室到患者的探索之旅
- DOI:
10.1016/j.molmed.2024.01.007 - 发表时间:
2024-03-01 - 期刊:
- 影响因子:13.800
- 作者:
Chiara Mozzetta;Vittorio Sartorelli;Pier Lorenzo Puri - 通讯作者:
Pier Lorenzo Puri
RETRACTED ARTICLE: Association of Ataxia Telangiectasia Mutated (ATM) gene mutation/deletion with Rhabdomyosarcoma
- DOI:
10.1186/1476-4598-2-2 - 发表时间:
2003-01-03 - 期刊:
- 影响因子:33.900
- 作者:
Peilin Zhang;Kunjan S Bhakta;Pier Lorenzo Puri;Robert O Newbury;James R Feramisco;Jean Y Wang - 通讯作者:
Jean Y Wang
Nuclear factor-kappaB and cAMP response element binding protein mediate opposite transcriptional effects on the Flk-1/KDR gene promoter.
核因子-kappaB 和 cAMP 反应元件结合蛋白介导 Flk-1/KDR 基因启动子上相反的转录作用。
- DOI:
- 发表时间:
2000 - 期刊:
- 影响因子:20.1
- 作者:
B. Illi;Pier Lorenzo Puri;Liliana Morgante;M. Capogrossi;C. Gaetano - 通讯作者:
C. Gaetano
Retraction Note: Association of Ataxia Telangiectasia Mutated (ATM) Gene Mutation/Deletion with Rhabdomyosarcoma – retraction
- DOI:
10.1186/1476-4598-2-17 - 发表时间:
2003-01-01 - 期刊:
- 影响因子:33.900
- 作者:
Peilin Zhang;Kunjan S Bhakta;Pier Lorenzo Puri;Robert O Newbury;James R Feramisco;Jean Y Wang - 通讯作者:
Jean Y Wang
Pier Lorenzo Puri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('Pier Lorenzo Puri', 18)}}的其他基金
Role of Fbxw7-Mediated Proteasomal Degradation in Myofibers in Determining Muscle Stem Cell Pool Size
Fbxw7 介导的肌纤维蛋白酶体降解在确定肌肉干细胞库大小中的作用
- 批准号:
10438706 - 财政年份:2020
- 资助金额:
$ 65.3万 - 项目类别:
Role of Fbxw7-Mediated Proteasomal Degradation in Myofibers in Determining Muscle Stem Cell Pool Size
Fbxw7 介导的肌纤维蛋白酶体降解在确定肌肉干细胞库大小中的作用
- 批准号:
10206003 - 财政年份:2020
- 资助金额:
$ 65.3万 - 项目类别:
Denervation activated super-enhancers of pathogenic IL6-STAT3 feedforward loop in FAPs
FAP 中致病性 IL6-STAT3 前馈环的去神经激活超级增强子
- 批准号:
10177874 - 财政年份:2019
- 资助金额:
$ 65.3万 - 项目类别:
Denervation activated super-enhancers of pathogenic IL6-STAT3 feedforward loop in FAPs
FAP 中致病性 IL6-STAT3 前馈环的去神经激活超级增强子
- 批准号:
10410466 - 财政年份:2019
- 资助金额:
$ 65.3万 - 项目类别:
Denervation activated super-enhancers of pathogenic IL6-STAT3 feedforward loop in FAPs
FAP 中致病性 IL6-STAT3 前馈环的去神经激活超级增强子
- 批准号:
10634547 - 财政年份:2019
- 资助金额:
$ 65.3万 - 项目类别:
Dystrophin signaling and the epigenetic landscape of human iPSC-derived muscles
肌营养不良蛋白信号传导和人类 iPSC 衍生肌肉的表观遗传景观
- 批准号:
8774130 - 财政年份:2009
- 资助金额:
$ 65.3万 - 项目类别:
Dystrophin signaling and the epigenetic landscape of human iPSC-derived muscles
肌营养不良蛋白信号传导和人类 iPSC 衍生肌肉的表观遗传景观
- 批准号:
9330676 - 财政年份:2009
- 资助金额:
$ 65.3万 - 项目类别:
Dystrophin signaling and the epigenetic landscape of human iPSC-derived muscles
肌营养不良蛋白信号传导和人类 iPSC 衍生肌肉的表观遗传景观
- 批准号:
8897264 - 财政年份:2009
- 资助金额:
$ 65.3万 - 项目类别:
相似国自然基金
基于ATAC-seq与DNA甲基化测序探究染色质可及性对莲两生态型地下茎适应性分化的作用机制
- 批准号:
- 批准年份:2024
- 资助金额:0.0 万元
- 项目类别:省市级项目
利用ATAC-seq联合RNA-seq分析TOP2A介导的HCC肿瘤细胞迁移侵
袭的机制研究
- 批准号:
- 批准年份:2024
- 资助金额:0.0 万元
- 项目类别:省市级项目
面向图神经网络ATAC-seq模体识别的最小间隔单细胞聚类研究
- 批准号:62302218
- 批准年份:2023
- 资助金额:30.00 万元
- 项目类别:青年科学基金项目
基于ATAC-seq策略挖掘穿心莲基因组中调控穿心莲内酯合成的增强子
- 批准号:
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
基于单细胞ATAC-seq技术的C4光合调控分子机制研究
- 批准号:
- 批准年份:2021
- 资助金额:30 万元
- 项目类别:青年科学基金项目
基于ATAC-seq技术研究交叉反应物质197调控TFEB介导的自噬抑制子宫内膜异位症侵袭的分子机制
- 批准号:82001520
- 批准年份:2020
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
靶向治疗动态调控肺癌细胞DNA可接近性的ATAC-seq分析
- 批准号:81802809
- 批准年份:2018
- 资助金额:21.0 万元
- 项目类别:青年科学基金项目
运用ATAC-seq技术分析染色质可接近性对犏牛初级精母细胞基因表达的调控作用
- 批准号:31802046
- 批准年份:2018
- 资助金额:27.0 万元
- 项目类别:青年科学基金项目
基于ATAC-seq和RNA-seq研究CWIN调控采后番茄果实耐冷性作用机制
- 批准号:31801915
- 批准年份:2018
- 资助金额:24.0 万元
- 项目类别:青年科学基金项目
基于ATAC-seq高精度预测染色质相互作用的新方法和基于增强现实的3D基因组数据可视化
- 批准号:31871331
- 批准年份:2018
- 资助金额:59.0 万元
- 项目类别:面上项目
相似海外基金
Project #2 Integrated single-nucleus multi-omics (ATAC-seq+RNA-seq or chromatin accessibility + RNA-seq) of human TGs
项目
- 批准号:
10806548 - 财政年份:2023
- 资助金额:
$ 65.3万 - 项目类别:
A transposase system for integrative ChIP-exo and ATAC-seq analysis at single-cell resolution
用于单细胞分辨率综合 ChIP-exo 和 ATAC-seq 分析的转座酶系统
- 批准号:
10210424 - 财政年份:2018
- 资助金额:
$ 65.3万 - 项目类别:
EAPSI: Developing Single Nucleus ATAC-seq to Map the Ageing Epigenome
EAPSI:开发单核 ATAC-seq 来绘制衰老表观基因组图谱
- 批准号:
1714070 - 财政年份:2017
- 资助金额:
$ 65.3万 - 项目类别:
Fellowship Award
A cloud-based learning module to analyze ATAC-seq and single cell ATAC-seq data
基于云的学习模块,用于分析 ATAC-seq 和单细胞 ATAC-seq 数据
- 批准号:
10558379 - 财政年份:2001
- 资助金额:
$ 65.3万 - 项目类别: