Roles of the methylase NSD3 in neural crest migration and non-histone methylation
甲基化酶 NSD3 在神经嵴迁移和非组蛋白甲基化中的作用
基本信息
- 批准号:9259108
- 负责人:
- 金额:$ 2.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-02 至 2019-09-01
- 项目状态:已结题
- 来源:
- 关键词:Adrenal MedullaAmino AcidsAnimalsBiological AssayBrainCartilageCell Culture SystemCell Culture TechniquesCellsChick EmbryoCongenital AbnormalityCytoplasmic ProteinDataDefectDevelopmentDiseaseEmbryoEventFaceGene ExpressionGenesGoalsHeartHistone H3HistonesHumanIn Situ HybridizationKineticsLabelLeadLinkLysineMalignant NeoplasmsMass Spectrum AnalysisMediatingMelanoma CellMessenger RNAMetastatic MelanomaMethylationMethyltransferaseModelingMolecularMultipotent Stem CellsNeoplasm MetastasisNeural CrestNeural Crest CellNeuroblastomaNeuronsOutcomePathway interactionsPeripheral Nervous SystemPhenotypePlayPopulationPost-Translational Protein ProcessingPreventionProtein MethylationProteinsProteomicsRegulationResearchRoleSpinal CordStable Isotope LabelingStem cellsStructureTimeTransplantationVertebral columnWestern BlottingWorkbasebonecancer therapycell behaviorcell motilitycell typecleft lip and palatecraniofacialcraniofacial developmenthistone methyltransferasein vivoinnovationinsightknock-downlive cell imagingloss of functionmelanocytemelanomamigrationmutantnon-histone proteinnovelorofacial cleftpreventresearch studytargeted treatmentvertebrate embryos
项目摘要
PROJECT SUMMERY/ABSTRACT:
Neural crest cells, a multipotent stem cell-like population unique to vertebrate embryos, migrate great
distances during development to form a wide variety of different cell types including craniofacial cartilage and
bone, melanocytes, the adrenal medulla, and much of the peripheral nervous system. Defects in neural crest
cell migration result in craniofacial maladies such as orofacial clefts, and dysregulation of neural crest derived
cell types leads to a number of invasive cancers such as neuroblastoma. Recent work in the Gammill lab
identified NSD3 as the first lysine methyltransferase that is essential for neural crest gene expression and
migration. Although the known role of NSD3 is to dimethylate the 36th lysine residue of histone H3, depletion of
NSD3 does not significantly alter H3K36me2 occupancy on neural crest genes even though these genes are
no longer expressed. These results, as well as the cytoplasmic localization of NSD3 in migrating neural crest
cells, the importance of cytoplasmic protein methylation during neural crest migration, and increasing evidence
that “histone” methyltransferases can methylate additional non-histone proteins, leads to the hypothesis that
NSD3 methylates non-histone targets in order to regulate neural crest cell migration and gene expression. To
explore this hypothesis, this proposal aims to define the essential role of NSD3 during cell migration in cell
culture and in chick embryos by characterizing NSD3 non-histone targets and the migratory features regulated
by their methylation. This will be accomplished by (1) defining the specific aspects of migration that are
defective in NSD3 knockdown cells, (2) identifying non-histone proteins methylated by NSD3 through mass
spectrometry-based quantitative proteomics, and (3) assaying the requirement for NSD3 non-histone targets
during migration, and determining the importance of NSD3-dependent methylation for their function.
Accomplishing these goals will define a novel mode of regulation governing neural crest cell migration and
craniofacial development, and will reveal new functions and targets of NSD3. These results will reveal
unappreciated post-translational control over cell migration, will uncover a novel regulatory mechanism in
development, and will have important implications for efforts to prevent craniofacial birth defects and develop
treatments for metastasis.
项目总结/摘要:
神经嵴细胞是脊椎动物胚胎特有的多能干细胞样细胞群,
在发育过程中的距离,以形成各种不同的细胞类型,包括颅面软骨,
骨、黑素细胞、肾上腺髓质和周围神经系统的大部分。神经嵴缺陷
细胞迁移导致颅面疾病,如口面裂,以及神经嵴的失调,
细胞类型导致许多侵袭性癌症,例如神经母细胞瘤。Gammill实验室最近的工作
将NSD 3鉴定为神经嵴基因表达所必需的第一个赖氨酸甲基转移酶,
迁移尽管已知NSD 3的作用是使组蛋白H3的第36个赖氨酸残基二甲基化,但NSD 3的缺失可能导致组蛋白H3的第36个赖氨酸残基二甲基化。
NSD 3并不显著改变神经嵴基因上的H3 K36 me 2占有率,即使这些基因是
不再表达。这些结果以及NSD 3在迁移神经嵴中的细胞质定位
细胞,细胞质蛋白甲基化在神经嵴迁移过程中的重要性,以及越来越多的证据表明,
“组蛋白”甲基转移酶可以甲基化额外的非组蛋白蛋白,这导致了这样的假设,
NSD 3甲基化非组蛋白靶标以调节神经嵴细胞迁移和基因表达。到
为了探索这一假说,该提议旨在确定NSD 3在细胞迁移过程中的重要作用,
通过表征NSD 3非组蛋白靶点和调节的迁移特征,
它们的甲基化。这将通过以下方式实现:(1)定义迁移的具体方面,
在NSD 3敲除细胞中有缺陷,(2)通过质谱鉴定被NSD 3甲基化的非组蛋白蛋白质
基于光谱的定量蛋白质组学,以及(3)测定对NSD 3非组蛋白靶点的需求
在迁移过程中,并确定NSD 3依赖性甲基化对其功能的重要性。
实现这些目标将定义一种新的调节神经嵴细胞迁移的模式,
颅面发育,并将揭示新的功能和NSD 3的目标。这些结果将揭示
对细胞迁移的翻译后控制,将揭示一种新的调控机制,
发展,并将有重要的影响,努力防止颅面出生缺陷和发展
转移的治疗。
项目成果
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