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Establishment of the meiotic cell cycle program through post-transcriptional regulation by MEIOC and YTHDC2

通过 MEIOC 和 YTHDC2 的转录后调控建立减数分裂细胞周期程序

基本信息

批准号：
9892137
负责人：
Maria Mikedis
金额：
$ 13.68万
依托单位：
WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-05 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892137
关键词：
Affect Aneuploidy Animal Model Binding Cell Cycle Cell Cycle Progression Cell Cycle Regulation Characteristics Chromosome Segregation Chromosomes Complex Congenital Abnormality Cyclins DNA biosynthesis Defect Development Diploidy Event Exhibits Failure Female Fertility Genes Genetic Recombination Genetic Transcription Germ Cells Germ Lines Goals Haploidy Health Hela Cells Human Infertility Knowledge Lead Length Life Malignant Neoplasms Mammals Mediating Meiosis Meiotic Prophase I Messenger RNA Metaphase Mitosis Mitotic Mitotic Prophase Modification Molecular Molecular Abnormality Mus Organism Outcome Post-Transcriptional Regulation Pregnancy Preventive treatment Prophase Proteins Publishing RNA Regulation Research Sampling Series Spontaneous abortion Testing Transcript Translational Repression Translations Ubiquitination Up-Regulation Work base cancer therapy cell transformation chromosome missegregation egg insight male predictive modeling premature prevent programs protein expression sperm cell

项目摘要

PROJECT SUMMARY/ABSTRACT Diploid germ cells are transformed into haploid gametes via the reductive division of meiosis. After meiotic DNA synthesis, germ cells enter meiotic prophase I, which distinguishes itself from mitotic prophase by two major characteristics. First, meiotic prophase I is dramatically longer than mitotic prophase. Second, meiotic prophase I involves an intricate series of chromosomal events that contribute to the establishment of the haploid state. The extended length of prophase I is critical for the completion of these chromosomal events, as premature exit from prophase I causes recombination defects and chromosome mis-segregation. In mammals, meiotic prophase I is prolonged by Meioc and Ythdc2. In the absence of either gene in both males and females, meiotic germ cells fail to complete meiotic prophase I and prematurely enter an abnormal metaphase before ultimately apoptosing. Several preliminary observations suggest that MEIOC and YTHDC2 function as a complex to post-transcriptionally regulate cell cycle factors within meiotic germ cells. MEIOC and YTHDC2 are first expressed in the germ line at meiotic initiation, and they interact with one another as well as with an overlapping set of transcripts, including key cell cycle regulators. These targets are enriched for the RNA modification N6-methyladenosine (m6A), which is preferentially recognized by YTHDC2's YTH domain and which is used to target and post-transcriptionally regulate RNA. In the absence of Meioc, MEIOC and YTHDC2's targets exhibit reduced stability. Changes in transcript stability are oftentimes accompanied by changes in translation, and in HeLa cells, YTHDC2 enhances translational efficiency while decreasing mRNA abundance. However, it remains unknown whether MEIOC and YTHDC2 affect translation in meiotic germ cells. This proposal will test the hypothesis that MEIOC and YTHDC2 function as a complex to recognize and translationally regulate m6A-modified mRNA in order to establish a meiosis-specific cell cycle program. This hypothesis will be tested via three specific aims. The first aim will assess MEIOC's ability to affect YTHDC2's interactions with RNA, particularly cell cycle-related transcripts, by identifying the transcripts that YTHDC2 binds to in the presence and absence of Meioc. In addition, whether m6A contributes to MEIOC and YTHDC2's ability to interact with RNA will also be assessed. The second aim will identify the translational changes that occur as germ cells transition from mitosis to meiosis, as well as between wild-type and Meioc-null samples. In particular, this aim will determine whether cell cycle factors are translationally repressed at the onset of meiosis and by the upregulation of Meioc. The third aim will determine whether MEIOC and YTHDC2 are continuously required during meiotic prophase I to prevent precocious cell cycle progression, as well as identify the mechanistic regulation behind this putative requirement. Collectively, these fundamental studies on MEIOC and YTHDC2's regulation of the length of meiotic prophase I will provide key insights into the establishment and regulation of the meiotic cell cycle program, with broader implications for fertility, development, and cancer.

项目总结/文摘