How does neuronal contact mediate astrocyte transcriptional maturation?
神经元接触如何介导星形胶质细胞转录成熟?
基本信息
- 批准号:10748163
- 负责人:
- 金额:$ 4.06万
- 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:2023-09-01 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdhesionsAstrocytesBar CodesBinding SitesBrainCRISPR-mediated transcriptional activationCell Adhesion MoleculesCell NucleusCellular biologyChIP-seqChromatinChromatin Remodeling FactorCoculture TechniquesComplexDNADataDevelopmentDoctor of PhilosophyEP300 geneEnzymesEpigenetic ProcessFibroblastsFlow CytometryFollow-Up StudiesFutureGene ExpressionGene Expression RegulationGenesGenetic TranscriptionGenomeGenus MenthaHistonesHomeostasisImmunoprecipitationImpairmentInfiltrationKnock-outKnockout MiceKnowledgeLifeLinkLoxP-flanked alleleMLL geneMeasuresMediatingMethanolMethodsMethylationMethyltransferaseModificationMolecularMorphogenesisMorphologyMusNatureNeurodevelopmental DisorderNeurogliaNeuronsNeuropilRattusSignal TransductionSynapsesTechniquesTestingTrainingWild Type MouseWorkautism spectrum disordercell typechromatin immunoprecipitationchromatin modificationepigenetic regulationexperienceexperimental studygenetic manipulationgenomic locushistone methyltransferasehistone modificationindexingmembernerve stem cellneurogenesisneuroligin 2neuronal circuitrynoveloverexpressionpharmacologicpostnatalpreventsynaptic functionsynaptogenesistranscriptometranscriptome sequencing
项目摘要
ABSTRACT
Developing a healthy functioning brain depends on the coordination of neuronal circuit formation by glial cells
called astrocytes. Previous work has shown that astrocytes, born from the same neural stem cells after the end
of neurogenesis, require contact with neurons to mature morphologically, functionally, and transcriptionally.
Astrocytic expression of the cell adhesion molecule neuroligin 2 (Nlgn2) is necessary for neuronal contact-
dependent astrocyte morphogenesis and synaptogenesis. These findings led us to investigate how neuronal
contact mediates astrocyte morphogenesis and synaptogenic functions. To address this question, we performed
multiplexed indexed T7 chromatin immunoprecipitation (MintChIP) sequencing to measure histone modifications
across the astrocyte genome. These experiments found that the chromatin modification landscape changes
significantly over postnatal astrocyte development. Interestingly, when we measured histone modifications in
astrocytes from Nlgn2 KO mice, we found a substantial decrease in the H3K4me1 and H3K4me3 modifications
compared to wildtype astrocytes. Based on these preliminary findings, this proposal will test the hypothesis
that epigenetic histone modifications are the mechanistic link between neuronal contact and astrocyte
transcriptional maturation. Specifically, aim 1 will test how histone modifications and transcriptional maturation
change when astrocytes are cultured with or without neurons and whether inhibiting histone-modifying enzymes
is sufficient to prevent astrocyte transcriptional maturation. Aim 2 will investigate the molecular mechanisms of
Nlgn2-dependent astrocyte transcriptional maturation. In particular, we will test the hypothesis that the chromatin
remodeler Chd8 is required for Nlgn2-dependent H3K4 methylation and that preventing this H3K4 methylation
through astrocyte-specific Chd8 knockout will prevent astrocyte transcriptional maturation. The successful
completion of these aims will determine the extent to which histone modifications regulate astrocyte maturation
and further our understanding of the molecular mechanism responsible for Nlgn2-induced gene expression
changes in astrocytes. These findings will also be highly relevant to future work in neurodevelopmental disorders
as astrocyte-regulated synaptogenesis, and epigenetic regulation of gene expression are emerging as prominent
aspects of conditions like autism spectrum disorders. Finally, this project will provide an excellent training
experience for Mr. Justin Savage through its intersection of epigenetics and glial cell biology.
摘要
发展健康的大脑功能有赖于神经胶质细胞对神经元回路形成的协调
叫做星形胶质细胞。以前的工作表明,星形胶质细胞出生后,结束于相同的神经干细胞
对于神经发生,需要与神经元接触才能在形态、功能和转录上成熟。
星形细胞表达细胞黏附分子神经连接蛋白2(Nlgn2)是神经元接触所必需的。
依赖星形胶质细胞的形态发生和突触发生。这些发现引导我们研究神经元是如何
接触调节星形胶质细胞的形态发生和突触发生功能。为了解决这个问题,我们执行了
多重索引T7染色质免疫沉淀(MintChip)测序法测定组蛋白修饰
整个星形细胞基因组。这些实验发现,染色质修饰的景观发生了变化
显著超过出生后星形胶质细胞的发育。有趣的是,当我们在
Nlgn2KO小鼠星形胶质细胞,我们发现H3K4me1和H3K4me3修饰显著减少
与野生型星形胶质细胞相比。基于这些初步发现,这项提议将检验这一假设
表观遗传组蛋白修饰是神经元接触和星形胶质细胞之间的机制联系
转录成熟。具体地说,目标1将测试组蛋白修饰和转录成熟
星形胶质细胞加或不加神经元培养时的变化以及是否抑制组蛋白修饰酶
足以阻止星形胶质细胞转录成熟。Aim 2将研究其分子机制。
Nlgn2依赖的星形胶质细胞转录成熟。特别是,我们将测试染色质的假设
依赖于Nlgn2的H3K4甲基化需要重构剂CHD8,并防止这种H3K4甲基化
通过星形胶质细胞特异性的CHD8基因敲除将阻止星形胶质细胞转录成熟。成功者
这些目标的完成将决定组蛋白修饰调控星形胶质细胞成熟的程度。
进一步了解了Nlgn2诱导基因表达的分子机制
星形胶质细胞的变化。这些发现也将与神经发育障碍的未来工作高度相关。
作为星形胶质细胞调节的突触发生和基因表达的表观遗传调节正日益突出
自闭症谱系障碍等疾病的各个方面。最后,这个项目将提供一个很好的培训
贾斯汀·萨维奇先生通过其交叉的表观遗传学和神经胶质细胞生物学的经验。
项目成果
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Justin Savage其他文献
Justin Savage的其他文献
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