Gene Regulatory Non-Coding RNAs in the Human Heart
Gene Regulatory Non-Coding RNAs in the Human Heart
批准号:
10460639
负责人:
Ivan Paul Moskowitz
金额:
$55.51万
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
项目状态:
已结题
起止时间:
2019-08-17 至 2023-07-31
关键词:
AddressApplications GrantsArchitectureBiochemistryBiologyCRISPR/Cas technologyCardiacCardiac MyocytesCardiovascular systemCell Culture TechniquesCellsChromatinChromosomesCodeDependenceDevelopmentDiseaseEnhancersEvaluationGene ActivationGene ExpressionGene Expression RegulationGenesGeneticGenetic Enhancer ElementGenetic TranscriptionHeartHumanHuman GeneticsInvestigationLaboratoriesLengthMeasuresMediatingMethodsMolecularMolecular GeneticsMolecular ProbesMusPlayPropertyPublishingRNARegulator GenesRegulatory ElementResearch PersonnelRoleTestingTranscription CoactivatorTranscriptional ActivationTranscriptional RegulationUntranslated RNAVariantWorkbasechromatin modificationexperimental studygene regulatory networkgenome-wideheart functionheart rhythmin vivoinduced pluripotent stem cellinduced pluripotent stem cell derived cardiomyocytesinsightnovelnovel strategiespromotertooltranscription factor
中文摘要
这项合作提议来自一位心脏分子遗传学家和一位
英文摘要
This collaborative proposal from a cardiac molecular geneticist and a
RNA-chromatin biochemist will investigate chromatin associated and
transcription factor dependent non-coding RNAs (ncRNAs) as essential
components of a cardiac regulatory network. We have applied a novel approach
for identification of functional long non-coding RNAs (lncRNAs) and the
enhancers that comprise gene regulatory networks. Using transcription factor-
dependence, we identified ncRNAs as markers of cis-regulatory elements
essential for a mouse cardiac rhythm gene regulatory network. This approach
identified exceptionally strong enhancers, and their associated ncRNA are
chromatin-bound and required for enhancer function. This proof of principal sets
the stage for the investigation of lncRNAs and their associated enhancers in
human cardiac gene regulatory networks. We posit that application of our
approach to human cardiomyocytes will allow identification of a functional class
of human heart enhancer-associated lncRNAs and cis-regulatory elements
(CREs) essential for the expression of human cardiac rhythm control genes. In
the first specific aim, we will interrogate a set of lncRNAs defined by their TF-
dependence and chromatin localization for their requirement for CRE activity and
target gene expression. In the second aim, we will utilize novel molecular tools
to probe the molecular mechanisms whereby the lncRNAs modulate gene
expression. Together these interconnected aims rely on the complementary and
non-overlapping expertise of the collaborative investigators to address a highly
significant problem in ncRNA biology. These hypotheses are applicable to
human genetics, transcriptional regulation, and RNA biology, and therefore may
have impact both within cardiovascular genetics and more broadly within human
molecular genetics.
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会议论文
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