Center for 3D Structure and Physics of the Genome
基因组 3D 结构和物理中心
基本信息
- 批准号:9021492
- 负责人:
- 金额:$ 75.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-30 至 2020-07-31
- 项目状态:已结题
- 来源:
- 关键词:BehaviorBerylliumBiologicalBiological ProcessCell CycleCell Differentiation processCell LineCell physiologyCellsChromatinChromatin StructureChromosome StructuresComputer SimulationDataData AnalysesData SetDevelopmentElementsEngineeringEnzymesEpigenetic ProcessFibroblastsFluorescence MicroscopyGenerationsGenesGenetic TranscriptionGenomeGenomicsGoalsHigher Order Chromatin StructureHistonesHumanImageImaging DeviceImaging TechniquesIn SituIndiumIndividualLeadLifeLigationMS2 coat proteinMaintenanceMapsMeasuresMethodsMicroscopyMiningModelingMutationOutputPatternPhysicsPlayProcessProteinsReagentRegulationReporterReporter GenesRepressionResolutionRoleShapesSiteStructureSystemTechniquesTestingTranscriptTransplantationUntranslated RegionsValidationVariantWritingbasedata modelinggenome editinghistone modificationhuman embryonic stem cellinsightmolecular imagingnucleasephotoactivationphysical modelpredictive modelingpromoterresearch studystemtechnology developmentthree dimensional structuretooltranscriptome sequencing
项目摘要
Project Summary – Biological Validation
The validity of the Reference Interaction Map from Components 2 and 3, which rely primarily on ligation-based
proximity mapping, will be assessed through independent methods testing genomic topology and its dynamics
during cell cycle and cell differentiation. In addition, the correlations between topological features and other
processes (e.g. local transcription rate, histone modifications, etc.) will imply functional roles for these features
that need to be evaluated. We will use powerful imaging techniques to test and further elaborate the genomic
structure and dynamics within our cellular systems. In addition, the direct perturbation of elements of specific
topological features will define their biological roles in the cellular processes under study.
To pursue these goals, we will develop a core set of tools and reagents and characterize a selected small
number of TADs in depth. TADs from differentiating hESCs and from dividing fibroblasts will be selected for
these analyses based on their dynamic topological behaviors and on the presence of embedded genes with
dynamic expression patterns. By validating and perturbing topological features in both human ESCs and
fibroblasts, we will be able to compare and contrast the similarities and differences in the behavior of these
systems. These experiments should help define the basic grammar that underlies the formation, maintenance
and dissolution of topological interactions.
In Aim 1, we will establish clonal hESC and fibroblast “imaging” lines, derived from the same lines that are
being mapped and analyzed by the consortium, that harbor integrated imaging tools (e.g. nuclease-dead Cas9
[dCas9] variants tethered to fluorescent proteins). These cell lines will be used to (i) image dynamic TADs
using multiple, independent methods to test whether their visible behavior is consistent with the structures and
transitions inferred from sequencing approaches, and to (ii) measure the TAD-specific transcriptional
consequences of dynamic topological behavior, as well as the topological consequences of dynamic
transcriptional behavior. In Aim 2, we will engineer mutations in TAD boundaries and intra-TAD topological
elements within these imaging cell lines, and use both imaging and molecular analyses to test the roles of the
altered sequences in forming or maintaining genome topology. In Aim 3, we will use dCas9 variants fused to
histone modification enzymes to define the topological and functional effects of “writing” or “erasing” specific
chromatin marks within and around individual TADs. In addition we will probe the requirements for creating
new topological features through the generation of artificial looping interactions via dCas9-interaction domains.
The dataset generated through these studies will allow the more accurate parameterization of the
computational models used to quantitatively represent and interpret the Reference Interaction Map as well as
provide critical insights into the biological functions of the topological features contained within the map.
项目摘要-生物验证
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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ERIK J. SONTHEIMER的其他文献
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$ 75.66万 - 项目类别:
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利用天然 Cas9 抑制剂增强基因组编辑技术
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- 资助金额:
$ 75.66万 - 项目类别:
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真细菌基于序列的病毒和质粒抗性机制
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- 资助金额:
$ 75.66万 - 项目类别:
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