Dnmt3b activities in mouse development
Dnmt3b 在小鼠发育中的活性
基本信息
- 批准号:10621334
- 负责人:
- 金额:$ 30.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAssisted Reproductive TechnologyBirthCellsClinicalComplexConceptionsDNADNA MethylationDNA Modification MethylasesDNA Transposable ElementsDNMT3B geneDNMT3aDataDefectDevelopmentDiseaseDown-RegulationEmbryoEmbryonic DevelopmentEnhancersEnzymesEpiblastEpigenetic ProcessEthicsFamilyFertilization in VitroFutureGene ExpressionGene Expression RegulationGenesGenetic TranscriptionGenomeGenomic ImprintingGenomic SegmentGenomicsHealthHumanHuman Cell LineImmunoprecipitationIn VitroIndividualKnock-outKnockout MiceKnowledgeLarge Intestine CarcinomaLongitudinal StudiesMalignant Epithelial CellMeasuresMediatingMedicineMethylationMethyltransferaseModelingModificationMolecularMolecular AnalysisMusPathogenesisPhenotypePhysiologicalPhysiological ProcessesPlayPre-implantation Embryo DevelopmentPreventive careProceduresProcessProteinsReportingRoleTechniquesTestingTimeTissue-Specific Gene ExpressionTissuesTotipotencyTranscriptional RegulationWestern BlottingX Inactivationdemethylationembryonic stem cellepigenomegenetic approachgenome wide methylationgenome-widegenomic locushistone modificationimplantationimprintin vivomethylation patternmouse developmentnovel therapeutic interventionpluripotencypostnatal developmentprenatalpreventpromoterrecruittranscriptome sequencing
项目摘要
DNA methylation is an epigenetic modification involved in transcriptional regulation of genes involved in
development and differentiation, and its deregulation contributes to human pathogenesis. It is catalyzed by the
family of DNA methyltransferases including catalytically active Dnmt1, Dnmt3a, Dnmt3b. DNA methylation
plays a major role in preimplantation development in mice. To establish a new epigenome, the mouse zygotic
genome undergoes epigenetic reprogramming, including global DNA demethylation at the 8-cell stage. Upon
implantation, a wave of de novo methylation in epiblast cells mediated by de novo enzymes Dnmt3a and
Dnmt3b results in new methylation patterns maintained by Dnmt1 that form a basis for tissue-specific
expression and differentiation.
Dnmt3b regulates developmental and imprinted genes, X chromosome inactivation, pericentromeric regions,
gene bodies and other genomic regions. Its importance in mouse development was demonstrated by
embryonic lethality of Dnmt3b-/- mice. We recently found that Dnmt3bCI/CI mice expressing catalytically inactive
Dnmt3bCI protein survived both pre- and postnatal development. Molecular analysis suggested that accessory
function - the ability to recruit other Dnmts to proper genomic loci – of Dnmt3b rather than its catalytic activity,
is important for methylation and survival. Here we hypothesize that Dnmt3b is a multifaceted protein whose
various activities involved in methylation affect pre- and postnatal development and are critical to prevent
disease formation in mice. To test this hypothesis, in Aim 1 we analyze global methylation and expression at
different stages of development in mice lacking various Dnmt activities to determine the scope of Dnmt3b’s
accessory function in Dnmt3a-mediated de novo methylation in vivo as well as regulation of transcription of
various genomic features including gene bodies, germline genes and transposons. In Aim 2, will test the ability
of Dnmt3b to complex with other Dnmts and contribute to de novo methylation induced by other Dnmts in
Dnmt1-/-;Dnmt3a-/-;Dnmt3b-/- triple knockout mouse embryonic stem cells. In addition, we will genetically test
the importance of Dnmt3a and Dnmt3l for Dnmt3b’s accessory function and validate our data in a human cell
line. In Aim 3, we will perform longitudinal study of Dnmt3b+/+ and Dnmt3bCI/CI mice conceived through the use
of in vitro fertilization (IVF) technique to analyze disease development, Dnmt levels, the rate of methylation and
gene expression errors, as well as their persistence over time.
Collectively, our studies will reveal physiological relevance of Dnmt3b activities in mouse development,
uncover basic mechanisms utilizing Dnmt3b functions and their involvement in IVF. Our results could result in
changes in Assisted Reproductive Technologies (ART) and affect the focus of preventive care for ART-
conceived individuals.
DNA甲基化是一种表观遗传修饰,参与基因的转录调控,
发育和分化,其失调有助于人类发病机制。它是由
DNA甲基转移酶家族,包括催化活性的Dnmt 1、Dnmt 3a、Dnmt 3b。DNA甲基化
在小鼠着床前发育中起主要作用。为了建立一个新的表观基因组,
基因组经历表观遗传重编程,包括8细胞阶段的整体DNA去甲基化。后
植入,由从头酶Dnmt 3a介导的外胚层细胞中的从头甲基化波,
Dnmt 3b导致Dnmt 1维持的新甲基化模式,这些模式形成了组织特异性甲基化的基础。
表达和分化。
Dnmt 3b调节发育和印记基因,X染色体失活,着丝粒周围区域,
基因体和其他基因组区域。它在小鼠发育中的重要性被证明是
Dnmt 3b-/-小鼠的胚胎致死率。我们最近发现,Dnmt 3bCI/CI小鼠表达的催化失活
Dnmt 3bCI蛋白在出生前和出生后的发育中都存活。分子分析表明
Dnmt 3b的功能--将其他Dnmt募集到适当基因组位点的能力--而不是其催化活性,
对甲基化和存活很重要。在这里,我们假设Dnmt 3b是一种多面蛋白,
参与甲基化的各种活动影响产前和产后发育,
在小鼠中形成疾病。为了验证这一假设,在Aim 1中,我们分析了在2000年至2010年期间的总体甲基化和表达。
缺乏各种Dnmt活性的小鼠的不同发育阶段,以确定Dnmt 3b的范围
在体内Dnmt 3a介导的从头甲基化中的辅助功能以及
各种基因组特征,包括基因体、生殖系基因和转座子。在目标2中,将测试
Dnmt 3b与其他Dnmts复合,并有助于由其他Dnmts诱导的从头甲基化,
Dnmt 1-/-; Dnmt 3a-/-; Dnmt 3b-/-三重敲除小鼠胚胎干细胞。此外,我们还将进行基因测试,
Dnmt 3a和Dnmt 3l对于Dnmt 3b辅助功能的重要性,并验证我们在人类细胞中的数据
线在目的3中,我们将对通过使用Dnmt 3b +/+和Dnmt 3bCI/CI小鼠进行纵向研究。
体外受精(IVF)技术,以分析疾病发展,Dnmt水平,甲基化率和
基因表达错误,以及它们随时间的持续性。
总的来说,我们的研究将揭示Dnmt 3b活性在小鼠发育中的生理相关性,
揭示利用Dnmt 3b功能的基本机制及其在IVF中的参与。我们的结果可能会导致
辅助生殖技术(ART)的变化,并影响ART预防护理的重点-
设想的个人。
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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Rene Opavsky其他文献
Rene Opavsky的其他文献
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{{ truncateString('Rene Opavsky', 18)}}的其他基金
The Tumor Suppressor Function of Dnmt3a in Chronic Lymphocytic Leukemia
Dnmt3a在慢性淋巴细胞白血病中的抑癌作用
- 批准号:
9233057 - 财政年份:2016
- 资助金额:
$ 30.5万 - 项目类别:
The Tumor Suppressor Function of Dnmt3a in Chronic Lymphocytic Leukemia
Dnmt3a在慢性淋巴细胞白血病中的抑癌作用
- 批准号:
9382528 - 财政年份:2016
- 资助金额:
$ 30.5万 - 项目类别:
MECHANISM OF ABERRANT DNA METHYLATION IN MOUSE LYMPHOMAGENESIS
小鼠淋巴细胞发生中异常 DNA 甲基化的机制
- 批准号:
8360440 - 财政年份:2011
- 资助金额:
$ 30.5万 - 项目类别:
MECHANISM OF ABERRANT DNA METHYLATION IN MOUSE LYMPHOMAGENESIS
小鼠淋巴细胞发生中异常 DNA 甲基化的机制
- 批准号:
8168389 - 财政年份:2010
- 资助金额:
$ 30.5万 - 项目类别:
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