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
• 负责人: Swathi Arur
• 金额: $ 40.5万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10673715
• 关键词: Area; Arginine; Biogenesis; Biological Assay; Biology; Birth; CRISPR/Cas technology; Caenorhabditis elegans; Cell Culture System; Cells; Congenital Abnormality; Development; Disease; Embryo; Embryonic Development; Endometrial Carcinoma; Event; Generations; Growth Factor; Human; Human Biology; Image; Infertility; Investigation; Knowledge; Light; Link; Malignant Neoplasms; Mammalian Cell; Mammals; Mediating; Meiosis; Methods; Methylation; Modeling; Morphogenesis; Oocytes; Phosphorylation; Population; Process; Proteome; Proteomics; Puberty; RNA; RNA Degradation; Regulation; Reproduction; Research; Role; Signal Transduction; Small RNA; Sterility; Untranslated RNA; Work; exosome; genome editing; human female; in vivo Model; mouse model; next generation sequencing; oocyte quality; sperm cell; transcriptome

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.

项目总结

项目成果

sart-3 functions to regulate germline sex determination in C. elegans .

SART-3功能可调节秀丽隐杆线虫中种系性别的确定。

• DOI: 10.17912/micropub.biology.000820
• 发表时间: 2023
• 期刊: microPublication biology
• 作者: Furuta, Tokiko;Arur, Swathi
• 通讯作者: Arur, Swathi