Transcriptional condensates, epigenetic editing and Rett Syndrome
转录凝聚体、表观遗传编辑和雷特综合征
基本信息
- 批准号:10013304
- 负责人:
- 金额:$ 96.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-15 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAdultAffectAllelesArchitectureBindingBinding SitesBiochemical ReactionBiological AssayBrainCell physiologyCellsChimeric ProteinsChromatinChromosomesClinical TrialsComplexCultured CellsDNADNA Binding DomainDNA Sequence AlterationDNA-Binding ProteinsDataDevelopmentDiseaseDisease ProgressionDisease modelEP300 geneEpigenetic ProcessEuchromatinFemaleGene ExpressionGenerationsGenesGenetic TranscriptionGoalsHeterochromatinHumanIn VitroLinkLiquid substanceMeCP2 Duplication SyndromeMediatingMental RetardationMethyl-CpG-Binding Protein 2MusMutant Strains MiceMutationNeurodevelopmental DisorderNeuronsPatientsPhasePhenotypePhysiologicalProtein RegionProteinsPsyche structureRecombinantsReporterRett SyndromeRoleSiteSymptomsSyndromeTestingTherapeuticTherapeutic InterventionTimeTranscription CoactivatorTranscription RepressorTransgenesTransgenic MiceTreatment EfficacyX Inactivationagedautism spectrum disorderbasebehavior influencecandidate identificationcohesindefined contributiondesigndisabilitydisease-causing mutationearly childhoodembryonic stem cellgene repressiongenetic corepressorgirlshuman embryonic stem cellin vivoinsightmouse developmentmutantnovel strategiesnovel therapeutic interventionnovel therapeuticsoverexpressionpostnatalpromoterprotein functionside effecttoolvector
项目摘要
Abstract
Rett syndrome (RTT) is a postnatal progressive neurodevelopmental disorder associated with severe mental
disability and autism-like syndromes that manifests in girls during early childhood, and is caused by mutation of
the X-linked DNA binding protein MeCP2 (Methyl CpG-binding Protein 2). Mice carrying null alleles of Mecp2
closely mimic symptoms seen in patients and are faithful models of the disease. Importantly, development of
RTT-like symptoms can be slowed or even halted in the adult following correction of a mutant Mecp2 allele by
transgene-mediated MeCP2 expression.
MeCP2 is one of the most abundant proteins in neurons, and most disease-causing mutations cluster in the
DNA binding domain (MBD) and in the transcription repression domain (TRD). However, the function of
MeCP2 remains enigmatic, with two major hypotheses having been proposed: (i) MeCP2 acts as repressor of
transcription or (ii) as an activator of transcription. Clearly, none of these proposed functions can fully explain
the complex phenotype of MeCP2 deficiency or overexpression leading to RTT or MECP2 Duplication
Syndrome. Based on our preliminary evidence we postulate that MeCP2’s primary function may be to
modulate the 3D chromosome architecture through condensate formation.
Components of both euchromatin and heterochromatin can form phase-separated condensates, which
provide a mechanism to compartmentalize and concentrate biochemical reactions within cells and are
produced by liquid-liquid phase separation driven by intrinsically disordered regions (IDRs) of proteins. MeCP2
protein contains a large IDR and we have obtained preliminary evidence that MeCP2 is involved in phase-
separated heterochromatin condensates. Thus, beyond MeCP2’s role as a repressor or activator of gene
expression, the protein may have a much wider and more complex role in the cell physiology and disease.
In this project we will define the contribution of MeCP2 to heterochromatic and euchromatic condensates in
normal and mutant neurons and analyze the effect of RTT causing mutations on LLPS. Our goal is to gain
insights into the function of MeCP2 as the basis for designing novel therapeutic approaches. Potential new
therapies based on this hypothesis will take time to develop into applications. To explore a more immediate
approach we will use epigenetic editing as a therapeutic tool to activate the inactive wt MECP2 allele located
on the inactive X chromosome. Most importantly, epigenetic editing will restore MeCP2 expression to exactly
wild type levels and thus avoid toxic consequences of MeCP2 overexpression. In contrast, other strategies
such as using vector-mediated MeCP2 transduction will invariably produce cells that overexpress MeCP2 and
thus will result in serious side effects as seen in patients with MECP2 duplication syndrome.
摘要
项目成果
期刊论文数量(0)
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RUDOLF JAENISCH其他文献
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{{ truncateString('RUDOLF JAENISCH', 18)}}的其他基金
Genetically engineered human pluripotent stem cells as a platform to define the b
基因工程人类多能干细胞作为定义 b 的平台
- 批准号:
9114690 - 财政年份:2014
- 资助金额:
$ 96.22万 - 项目类别:
Transcriptional condensates, epigenetic editing and Rett Syndrome
转录凝聚体、表观遗传编辑和雷特综合征
- 批准号:
10675642 - 财政年份:2014
- 资助金额:
$ 96.22万 - 项目类别:
An iPSC based platform for functionally assessing genetic and environmental risk
基于 iPSC 的平台,用于功能性评估遗传和环境风险
- 批准号:
8764379 - 财政年份:2014
- 资助金额:
$ 96.22万 - 项目类别:
Transcriptional condensates, epigenetic editing and Rett Syndrome
转录凝聚体、表观遗传编辑和雷特综合征
- 批准号:
10462550 - 财政年份:2014
- 资助金额:
$ 96.22万 - 项目类别:
Genetically engineered human pluripotent stem cells as a platform to define the b
基因工程人类多能干细胞作为定义 b 的平台
- 批准号:
8926472 - 财政年份:2014
- 资助金额:
$ 96.22万 - 项目类别:
An iPSC based platform for functionally assessing genetic and environmental risk
基于 iPSC 的平台,用于功能性评估遗传和环境风险
- 批准号:
9313959 - 财政年份:2014
- 资助金额:
$ 96.22万 - 项目类别:
Genetically engineered human pluripotent stem cells as a platform to define the b
基因工程人类多能干细胞作为定义 b 的平台
- 批准号:
8760558 - 财政年份:2014
- 资助金额:
$ 96.22万 - 项目类别:
Transcriptional condensates, epigenetic editing and Rett Syndrome
转录凝聚体、表观遗传编辑和雷特综合征
- 批准号:
10223990 - 财政年份:2014
- 资助金额:
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- 资助金额:
$ 96.22万 - 项目类别:
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