Mechanisms of heterochromatin targeting and epigenetic genome regulation
Mechanisms of heterochromatin targeting and epigenetic genome regulation
批准号:
9142004
负责人:
Aaron M. Johnson
金额:
$36.71万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-08-16 至 2021-05-31
关键词:
AddressBase PairingBiochemicalCell NucleusChromatinComplexDevelopmentDiseaseEpigenetic ProcessEventGene ClusterGene ExpressionGene Expression RegulationGene SilencingGene TargetingGenesGenetic TranscriptionGenomeGenomicsGoalsHeritabilityHeterochromatinHomeobox GenesHuman GenomeInvestigationJunk DNALeadLinkMalignant NeoplasmsMediatingModelingMolecularMolecular TargetNeoplasm MetastasisPathway interactionsPolycombProteinsProteomicsPublic HealthRNARNA SequencesRegulationRepressionResearchScaffolding ProteinSpecificityTranscriptUntranslated RNAhuman diseaseprogramsreconstitutionscaffold
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
The long-term goals of this research program are to determine at a molecular level how long noncoding
RNAs (lncRNAs) participate in chromatin-mediated gene silencing. Many lncRNAs act in the nucleus to
regulate gene expression through scaffolding of chromatin regulatory machinery. The identification of lncRNAs
far outpaces detailed investigations, hence the mechanisms that govern these lncRNA-mediated events are
not yet well-understood. We will address four major outstanding questions in the field: 1) How do lncRNAs
target specific regions of the genome? 2) Do lncRNAs require structural remodeling for activation of chromatin
repression machinery? 3) How can a lncRNA contribute to halting gene transcription? 4) What is the full-extent
that a lncRNA can scaffold protein interactions on chromatin? Our immediate goals are to focus on the model
lncRNA HOTAIR while longer-term goals will investigate additional lncRNAs for which much less is known.
HOTAIR is transcribed from one developmentally-regulated HOX gene cluster and regulates many genes in
trans through the Polycomb silencing complex PRC2. Our recent progress has identified a new key player in
dictating the specificity of HOTAIR function and has suggested a model where HOTAIR uses a protein
"matchmaker" to mediate RNA-RNA base-pairing interactions with the nascent transcripts of target genes. We
will approach this model using the questions framed above to uncover a new level of mechanistic detail for this
lncRNA. A multi-faceted approach will be used, merging biochemical reconstitution with cutting edge
proteomics and genomics, to uncover how lncRNAs use their reservoirs of RNA sequence information to target
and scaffold heterochromatin formation. These studies will generate a model for lncRNA mechanism in gene
regulation that may be broadly applicable to other lncRNA pathways. We will also highlight potential molecular
targets to disrupt the HOTAIR activity that promotes metastasis in many cancers.
Relevance to public health
Long noncoding RNAs are produced from regions of the human genome originally thought to be "junk" DNA.
Many lncRNAs participate in epigenetic mechanisms of gene regulation and mis-regulation can lead to
diseases such as cancer. LncRNAs are therefore clear candidates to provide a missing link to understanding
the molecular mechanisms of many human diseases for which there is a "hidden heritability" factor that has not
yet been identified.
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会议论文
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批准号:8132400
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财政年份:2010
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Comprehensive Characterization of Heterochromatin Domains
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批准号:8392028
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资助金额:$24.9万
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财政年份:2010
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依托单位:
Comprehensive Characterization of Heterochromatin Domains
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批准号:8424267
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资助金额:$23.64万
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财政年份:2010
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Comprehensive Characterization of Heterochromatin Domains
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批准号:8607964
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项目类别:
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资助金额:$24.27万
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财政年份:2010
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依托单位:
Mechanistic Studies of silent chromatin spreading
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批准号:7155848
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项目类别:
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资助金额:$4.4万
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财政年份:2006
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负责人:Aaron M. Johnson
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依托单位:
Mechanistic Studies of silent chromatin spreading
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批准号:7285996
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项目类别:
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资助金额:$4.6万
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财政年份:2006
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负责人:Aaron M. Johnson
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依托单位:
Mechanistic Studies of silent chromatin spreading
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批准号:7489331
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项目类别:
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资助金额:$4.88万
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财政年份:2006
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负责人:Aaron M. Johnson
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依托单位:
海外基金