High-throughput engineering of combinatorial chromatin signals and epigenetic cellular memory
组合染色质信号和表观遗传细胞记忆的高通量工程
基本信息
- 批准号:10739173
- 负责人:
- 金额:$ 17.36万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2028-07-31
- 项目状态:未结题
- 来源:
- 关键词:AreaBypassCatalogsCell divisionCellsChromatinClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsComplexDNA LibraryDNA SequenceDNMT3aDiseaseEngineeringEnhancersEpigenetic ProcessExhibitsFunctional disorderFutureGene ExpressionGene SilencingGenesGenetic TranscriptionGenomeGenomic medicineGenomicsGoalsGuide RNAHeritabilityHumanHuman GenomeInduced pluripotent stem cell derived neuronsK562 CellsLibrariesMemoryMentorsMessenger RNAMethodsMitoticMolecularMonitorN DomainNeurodegenerative DisordersPhysiologic pulseProteinsRegulationRegulatory ElementReportingRepressed MemoryRepressionResearchResearch PersonnelResourcesRibonucleoproteinsRiskRunningSamplingSignal TransductionSiteSpecificityTertiary Protein StructureTestingTherapeuticTrainingVariantcareercareer developmentcell typecellular transductionchromatin modificationcombinatorialconstitutive expressioncost effectiveepigenetic memoryepigenetic silencingepigenomicsfrontierfunctional genomicsgene therapygenetic regulatory proteingenomic locusimmunogenicityimprovedinnovationinsightinterestknowledge baseneurogeneticsnucleasepromoterprotein complexrecruitsuccesssynthetic biologysynthetic constructtargeted treatmenttau Proteinstherapeutic targettooltranscriptomics
项目摘要
PROJECT SUMMARY/ABSTRACT
A major frontier of genomic medicine is to convert annotations of disease-associated variants
and gene expression states into actionable therapeutic targets. Genomic sequence editing by
CRISPR/Cas has garnered heightened interest as potential therapeutics, but still carries risks of
off-target mutagenicity, and is less effective at targeting cis-regulatory elements, where the
majority of disease-associated variants reside. A conceptual alternative to DNA sequence
editing is to deliver a brief pulse of a synthetic therapeutic that can trigger memorized silencing
of target promoters and enhancers in a "hit-and-run" strategy, bypassing concerns of
mutagenicity associated with DNA sequence editing, and immunogenicity associated with
constitutive expression of CRISPR/Cas components. In practice, engineering sustained
epigenetic transcriptional silencing has had mixed success, but recent efforts demonstrate
that constructing specific combinations of chromatin signals -- broadly encompassing cis-
regulatory elements, regulatory protein complexes, and covalent chromatin modifications --
can be critical for success. However, existing tools for manipulating chromatin signals at high
throughput are limited in combinatorial capacity. This proposal builds the knowledge base and
generalizable CRISPR/Cas tools to overcome such limitations to enable systematic engineering
of epigenetic silencing memory across genomic loci in human cells. The results will pave the
way for future epigenetic therapeutics that expand the directly targetable portion of the human
genome, including cis-regulatory elements that can be highly specific with respect to cell types
and disease pathophysiology. To achieve these objectives, I am proposing to train in
CRISPR/Cas synthetic biology, functional genomics, single-cell methods and neurogenetics.
This training will be mentored by a co-mentorhsip team consisting of Dr. Luke Gilbert (UCSF,
Innovative Genomics Institute, and Arc Institute), Dr. Howard Chang (Stanford) and Dr. Thomas
Montine (Stanford), each providing critical intellectual and physical resources for specific areas
proposed in the training plan and my career development. My career goal is to conduct research
at the forefront of genome regulation and genomic medicine as an academic principle
investigator.
项目总结/摘要
基因组医学的一个主要前沿是转换疾病相关变异的注释
和基因表达状态转化为可操作的治疗靶点。基因组序列编辑
CRISPR/Cas作为潜在的治疗方法已经引起了高度的兴趣,但仍然存在风险,
脱靶致突变性,并且在靶向顺式调节元件时不太有效,其中
大多数与疾病相关的变异存在。DNA序列的概念替代
编辑是传递一种合成疗法的短暂脉冲,
目标启动子和增强子的“打了就跑”的策略,绕过了
与DNA序列编辑相关的致突变性和与
CRISPR/Cas组分的组成型表达。在实践中,工程持续
表观遗传转录沉默取得了好坏参半的成功,但最近的努力表明,
构建染色质信号的特定组合--广泛地包括顺式--
调控元件、调控蛋白复合物和共价染色质修饰--
对成功至关重要然而,现有的用于在高水平上操纵染色质信号的工具,
生产量受限于组合容量。该提案建立了知识库,
可推广的CRISPR/Cas工具来克服这些限制,以实现系统工程
在人类细胞中基因组位点的表观遗传沉默记忆。结果将铺平
未来表观遗传疗法的一种方式,扩大人类的直接靶向部分
基因组,包括对细胞类型具有高度特异性的顺式调控元件
和疾病病理生理学。为了实现这些目标,我建议培训
CRISPR/Cas合成生物学、功能基因组学、单细胞方法和神经遗传学。
这项培训将由卢克吉尔伯特博士(加州大学旧金山分校,
创新基因组学研究所和Arc研究所)、霍华德·张博士(斯坦福大学)和托马斯博士
蒙廷(斯坦福大学),每个提供关键的智力和物质资源的特定领域
在培训计划和我的职业发展建议。我的职业目标是进行研究
在基因组调控和基因组医学作为一个学术原则的前沿
调查员
项目成果
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