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
发育一个健康功能的大脑取决于神经胶质细胞形成神经元回路的协调
叫做星形胶质细胞。以前的工作表明,星形胶质细胞,出生后,从同一神经干细胞结束,
在神经发生中,需要与神经元接触以在形态、功能和转录上成熟。
星形胶质细胞表达细胞粘附分子神经连接素2(Nlgn 2)是神经元接触所必需的。
依赖星形胶质细胞形态发生和突触发生。这些发现让我们去研究神经元
接触介导星形胶质细胞形态发生和突触发生功能。为了解决这个问题,我们进行了
多重索引T7染色质免疫沉淀(MintChIP)测序以测量组蛋白修饰
整个星形胶质细胞基因组。这些实验发现,染色质修饰景观的变化
明显超过了出生后星形胶质细胞的发育。有趣的是,当我们测量组蛋白修饰时,
从Nlgn 2 KO小鼠的星形胶质细胞中,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。根据这些初步发现,本提案将检验这一假设
表观遗传组蛋白修饰是神经元接触和星形胶质细胞
转录成熟。具体来说,aim 1将测试组蛋白修饰和转录成熟
当星形胶质细胞与或不与神经元一起培养时,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。目的2将研究
Nlgn2依赖的星形胶质细胞转录成熟。特别是,我们将检验染色质
重塑Chd 8是Nlgn 2依赖性H3 K4甲基化所需的,并且可以阻止这种H3 K4甲基化
通过星形胶质细胞特异性Chd8敲除将阻止星形胶质细胞转录成熟。成功
这些目标的完成将决定组蛋白修饰调节星形胶质细胞成熟的程度
进一步了解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
由于星形胶质细胞调控的突触发生和基因表达的表观遗传调控正在成为突出的
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
通过表观遗传学和神经胶质细胞生物学的交叉,为贾斯汀·萨维奇先生提供了丰富的经验。
项目成果
期刊论文数量(0)
专著数量(0)
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Justin Savage其他文献
Justin Savage的其他文献
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