Project 1: Regulation of gene networks through cardiac transcription factor interaction with the nuclear membrane
项目1:通过心脏转录因子与核膜相互作用调节基因网络
基本信息
- 批准号:10471988
- 负责人:
- 金额:$ 57.97万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAdultAffectArchitectureCRISPR/Cas technologyCardiacCardiac MyocytesCardiac developmentCardiomyopathiesCellsChromatinChromatin Remodeling FactorCollaborationsComplexDataDevelopmental GeneDiseaseEmbryoEpigenetic ProcessEventFailureFibroblastsGATA4 geneGene ExpressionGene Expression RegulationGenesGenetic Enhancer ElementGenetic TranscriptionGenome engineeringGenomic SegmentGenomicsGlycineHeart DiseasesHumanImpairmentIndividualInterventionInvestigationMapsMissense MutationMusMutationNatureNuclear EnvelopeNuclear PoreNuclear Pore ComplexNuclear Pore Complex ProteinsOutcomeOutputPeripheralPore ProteinsProcessProteinsRepressionRoleSerineSpecificityTBX5 proteinTestingTissuesbasecombinatorialcongenital heart disorderdisease-causing mutationgene networkgene regulatory networkgene repressiongenetic informationgenetic regulatory proteingenomic locushuman diseasein vivoinduced pluripotent stem cellinduced pluripotent stem cell derived cardiomyocytesmembermyocardinnovelnucleocytoplasmic transportprogramsprotein complexrecruitscaffoldstoichiometrytranscription factor
项目摘要
PROJECT SUMMARY/ABSTRACT
PROJECT 1
Cardiac development relies on the stepwise activation and repression of lineage-specific gene expression
programs. This process is regulated by conserved cardiac transcription factors (cTFs), such as NKX2.5,
GATA4, TBX5, MEF2C and Myocardin, which cooperate with one another and chromatin-remodeling
complexes to establish cellular identity by controlling gene regulatory networks. The critical nature of
cooperative interactions is highlighted by a heterozygous glycine-to-serine missense mutation in GATA4
(GATA4-G296S) that disrupts interaction with TBX5 and causes congenital heart disease (CHD). TBX5 and
GATA4 interact with the BAF complex of chromatin-remodeling proteins (investigated in Project 2), and
together, these factors promote cardiac reprogramming in embryos. Further addition of MEF2C and its co-
activator, Myocardin, (investigated in Project 3) reprograms adult cardiac fibroblasts into cardiomyocyte-like
cells. Our Preliminary Data revealed that TBX5 and GATA4 interact with several nucleoporins that constitute
the nuclear pore complex (NPC) at the nuclear membrane. Nucleoporins can control activation or silencing of
developmental genes by regulating the three-dimensional chromatin architecture, but how specific genomic
regions are recruited to the nuclear membrane remains unclear. Here, we will test the hypothesis that GATA4
and TBX5 interact in a lineage-specific fashion with NPC proteins to recruit genomic loci to the nuclear
membrane to regulate the transcriptional output during cardiac differentiation. We will use hiPSC-derived CMs
in which disruption of individual proteins or their interaction is possible using CRISPR/Cas9-based genome
engineering (supported by Core C), and validate the findings in vivo in mice. We propose that the defective
interaction between GATA4 and TBX5 disrupts the stoichiometry of the protein complex with nucleoporins
(supported by Core A) and, thereby, contributes to the altered cardiac transcriptional and epigenetic outcome
associated with disease (supported by Core B). Our specific aims are as follows: Aim 1) determine which
nuclear pore proteins interact and co-localize with TBX5 or GATA4 to establish the lineage-specific three-
dimensional genomic architecture in human cardiomyocytes and reprogrammed cardiomyocyte-like cells; Aim
2) determine the nature of enhancer elements localized to the NPC through interaction with TBX5 or GATA4,
and the related epigenetic and transcriptional consequences during cardiomyocyte differentiation and
reprogramming; and Aim 3) determine the effects of the human disease–causing mutation in GATA4 that
disrupts interaction with TBX5 on the 3D genomic architecture, the transcriptional and epigenetic states of loci
recruited to the nuclear membrane, and the interdependence of these events on physical interaction between
GATA4 and TBX5. These studies represent a novel investigation into the role for lineage-specific TFs in
regulating gene transcription by localization of specific genomic loci to the NPC and aim to open a new field in
understanding the flow of genetic information during CM lineage specification.
项目总结/文摘
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)
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DEEPAK SRIVASTAVA其他文献
DEEPAK SRIVASTAVA的其他文献
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{{ truncateString('DEEPAK SRIVASTAVA', 18)}}的其他基金
Small molecule therapeutic for calcific aortic valve disease
钙化性主动脉瓣疾病的小分子治疗
- 批准号:
10735711 - 财政年份:2023
- 资助金额:
$ 57.97万 - 项目类别:
Aortic Valve Disease: Mechanisms and Therapeutic Approaches
主动脉瓣疾病:机制和治疗方法
- 批准号:
10548842 - 财政年份:2020
- 资助金额:
$ 57.97万 - 项目类别:
Combinatorial Regulation of Gene Networks During Cardiac Development and Disease
心脏发育和疾病过程中基因网络的组合调控
- 批准号:
10471980 - 财政年份:2019
- 资助金额:
$ 57.97万 - 项目类别:
Project 1: Regulation of gene networks through cardiac transcription factor interaction with the nuclear membrane
项目1:通过心脏转录因子与核膜相互作用调节基因网络
- 批准号:
10245029 - 财政年份:2019
- 资助金额:
$ 57.97万 - 项目类别:
Combinatorial Regulation of Gene Networks During Cardiac Development and Disease
心脏发育和疾病过程中基因网络的组合调控
- 批准号:
10006031 - 财政年份:2019
- 资助金额:
$ 57.97万 - 项目类别:
Combinatorial Regulation of Gene Networks During Cardiac Development and Disease
心脏发育和疾病过程中基因网络的组合调控
- 批准号:
10245023 - 财政年份:2019
- 资助金额:
$ 57.97万 - 项目类别:
Project 1: Regulation of gene networks through cardiac transcription factor interaction with the nuclear membrane
项目1:通过心脏转录因子与核膜相互作用调节基因网络
- 批准号:
10006188 - 财政年份:2019
- 资助金额:
$ 57.97万 - 项目类别:
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