ERK-mediated regulation of non-coding RNAs during development and disease
发育和疾病过程中 ERK 介导的非编码 RNA 调节
基本信息
- 批准号:10487399
- 负责人:
- 金额:$ 40.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-10 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:AreaArginineBiogenesisBiological AssayBiologyBirthCRISPR/Cas technologyCaenorhabditis elegansCell Culture SystemCellsCongenital AbnormalityDevelopmentDiseaseEmbryoEmbryonic DevelopmentEndometrial CarcinomaEventGenerationsGrowth FactorHumanHuman BiologyImageInfertilityInvestigationKnowledgeLightLinkMalignant NeoplasmsMammalian CellMammalsMediatingMeiosisMethodsMethylationModelingMorphogenesisOocytesPhosphorylationPopulationProcessProteomeProteomicsPubertyRNARNA DegradationRegulationReproductionResearchRoleSignal TransductionSmall RNASterilityUntranslated RNAWorkgenome editinghuman femalein vivo Modelmouse modelnext generation sequencingoocyte qualitysperm celltranscriptome
项目摘要
PROJECT SUMMARY
Successful reproduction through the fusion of the sperm and oocyte is essential for the perpetuation of species.
In human females, oocytes complete meiosis I at birth, and enter a long period of meiotic II arrest until
onset of meiotic maturation at puberty. Because the oocytes are quiescent and arrested during this period,
RNAs are loaded into the developing oocytes prior to the arrest and these RNAs are critical for early
embryonic development. Mechanisms that regulate generation and protection (from degradation) of
maternal RNAs during the long meiotic arrest as well as mechanisms that regulate the degradation of these
RNAs in the embryo remain an active area of investigation. Our work in C. elegans and work from mammalian
models in the past few years turned the light on regulation of the maternal transcriptome which dictates oocyte
quality and impacts progeny development. Specifically, we uncovered a direct link between RAS/ERK growth
factor signaling and the small RNA biogenesis factors Dicer1, Drosha and DIS3 (an RNA exosomal component)
which regulates distinct populations of small non-coding RNAs and thus the maternal transcriptome and
proteome. We propose a model wherein ERK-mediated phosphorylation of Dicer1 (and a subsequent arginine
methylation of Dicer1), phosphorylation of Drosha and DIS3 results in a regulatory circuit that fine tunes the
generation of small non-coding RNAs in specific subsets and regulates the maternal and zygotic transcriptome
and proteome. We investigate this model in vivo during oocyte development and oocyte-to-embryo transition
using a combination of live imaging, next generation sequencing, single oocyte sequencing, mass spectrometric
and proteomic methods, CRISPR Cas9 genome editing and cell biological assays. We find that Dicer1, Drosha
and Dis3 are phosphorylated in mammals as well. Additionally, we identified arginine methylation of Dicer1
adjacent to the phosphorylation event in mammalian cell culture system. Given their conserved role in RNA
biology, reproduction and their aberrations associated with cancer onset and progression, we expect this work
to have direct relevance to human biology.
项目摘要
通过精子和卵母细胞融合的成功繁殖对于物种的延续至关重要。
在人类女性中,卵母细胞出生时就完成了减数分裂,并进入长期的减数分裂II直到
青春期减数分裂成熟的发作。由于卵母细胞在此期间被静止并逮捕
RNA在逮捕前将RNA装入发育中的卵母细胞,这些RNA对于早期至关重要
胚胎发展。调节生成和保护(从退化)的机制
母体RNA在长期减数分裂停滞期间以及调节这些降解的机制
胚胎中的RNA仍然是活跃的研究领域。我们在秀丽隐杆线虫中的工作,并从哺乳动物的工作
在过去的几年中,模型阐明了孕产妇转录组的调节,该转录组决定了卵母细胞
质量并影响后代发展。具体而言,我们发现了RAS/ERK增长之间的直接联系
因子信号传导和小的RNA生物发生因子DICER1,DROSHA和DIS3(RNA外泌体成分)
调节小型非编码RNA的不同种群,从而调节母体转录组和
蛋白质组。我们提出了一个模型,其中ERK介导的DICER1的磷酸化(以及随后的精氨酸
DICER1的甲基化,DROSHA和DIS3的磷酸化导致调节电路,以微调
在特定子集中生成小型非编码RNA,并调节母体和合子转录组
和蛋白质组。我们在卵母细胞发育和卵母细胞到胚胎过渡期间在体内研究了这个模型
结合实时成像,下一代测序,单个卵母细胞测序,质谱
和蛋白质组学方法,CRISPR CAS9基因组编辑和细胞生物学测定。我们发现Dicer1,Drosha
和DIS3在哺乳动物中也被磷酸化。此外,我们确定了DICER1的精氨酸甲基化
与哺乳动物细胞培养系统中的磷酸化事件相邻。鉴于它们在RNA中的保守作用
生物学,繁殖及其与癌症发作和进展相关的畸变,我们希望这项工作
与人类生物学有直接相关。
项目成果
期刊论文数量(0)
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{{ truncateString('Swathi Arur', 18)}}的其他基金
Spatio-temporal regulation of ERK signaling by phosphatases in the female germline
雌性种系中磷酸酶对 ERK 信号传导的时空调节
- 批准号:
10571433 - 财政年份:2023
- 资助金额:
$ 40.5万 - 项目类别:
2023 Developmental Biology Gordon Research Conference and Gordon Research Seminar
2023年发育生物学戈登研究会议暨戈登研究研讨会
- 批准号:
10683608 - 财政年份:2023
- 资助金额:
$ 40.5万 - 项目类别:
ERK-mediated regulation of non-coding RNAs during development and disease
发育和疾病过程中 ERK 介导的非编码 RNA 调节
- 批准号:
10673715 - 财政年份:2021
- 资助金额:
$ 40.5万 - 项目类别:
ERK mediated regulation of RbAp46/48 during female germ cell development
ERK 介导的雌性生殖细胞发育过程中 RbAp46/48 的调节
- 批准号:
10612853 - 财政年份:2020
- 资助金额:
$ 40.5万 - 项目类别:
ERK mediated regulation of RbAp46/48 during female germ cell development
ERK 介导的雌性生殖细胞发育过程中 RbAp46/48 的调节
- 批准号:
10388221 - 财政年份:2020
- 资助金额:
$ 40.5万 - 项目类别:
ERK mediated regulation of RbAp46/48 during female germ cell development
ERK 介导的雌性生殖细胞发育过程中 RbAp46/48 的调节
- 批准号:
10219320 - 财政年份:2020
- 资助金额:
$ 40.5万 - 项目类别:
Erk-mediated regulation of Dicer and Drosha function in C. elegans
Erk 介导的线虫 Dicer 和 Drosha 功能调节
- 批准号:
8729492 - 财政年份:2011
- 资助金额:
$ 40.5万 - 项目类别:
Erk-mediated regulation of Dicer and Drosha function in C. elegans
Erk 介导的线虫 Dicer 和 Drosha 功能调节
- 批准号:
8147376 - 财政年份:2011
- 资助金额:
$ 40.5万 - 项目类别:
Erk-mediated regulation of Dicer and Drosha function in C. elegans
Erk 介导的线虫 Dicer 和 Drosha 功能调节
- 批准号:
8323245 - 财政年份:2011
- 资助金额:
$ 40.5万 - 项目类别:
Erk-mediated regulation of Dicer and Drosha function in C. elegans
Erk 介导的线虫 Dicer 和 Drosha 功能调节
- 批准号:
8535274 - 财政年份:2011
- 资助金额:
$ 40.5万 - 项目类别:
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