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Elucidating the molecular basis of lncRNA evolution for mammalian dosage compensation

阐明哺乳动物剂量补偿的 lncRNA 进化的分子基础

基本信息

批准号：
10668360
负责人：
Sha Sun
金额：
$ 31.92万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
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：
2021-09-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668360
关键词：
Affect Animals Binding CRISPR/Cas technology Cells Chromosomes Code Conserved Sequence Data Deer Mouse Defect Development Diagnostic Disease Distant Dosage Compensation (Genetics)Dose Elements Embryo Deaths Engineering Evolution Experimental Models Failure Female Gene Cluster Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Transcription Genetic Variation Health Homologous Gene Human Hybrids In Vitro Knock-in Knowledge Length Link Malignant Neoplasms Mammals Maps Marsupialia Measures Mediating Methods Modeling Molecular Mus Nucleotides Pattern Peromyscus Phylogenetic Analysis Plants Prevention Primates Property Proteins RNA Reporting Research Rodent Role Sequence Alignment Sex Chromosomes Site Site-Directed Mutagenesis Structure System Transcript Transgenes Transgenic Mice Transgenic Organisms Untranslated RNA Variant Visualization X Chromosome X Inactivation Y Chromosome autosome blastomere structure developmental disease embryo cell embryonic stem cell epigenetic regulation fly gene product genetic evolution genetic sex determination human disease in vivo insight male mouse genome sex stem

项目摘要

ABSTRACT Genetic sex determination and sex chromosomes have evolved in both animals and plants. In mammals, males are XY and females are XX. Degeneration of the Y chromosome and the difference in the number of X- chromosome would lead to dose imbalance of X-linked gene products between male and female cells. To resolve this problem, various dosage compensation mechanisms have evolved in heterogametic species. In mammals, one of the two X chromosomes is transcriptionally silenced in females during X-inactivation. While X-inactivation has been extensively studied as a paradigm for epigenetic regulation of sex chromosomes, it is largely controlled by long noncoding RNAs (lncRNAs) that remain elusive for their role in the evolution of dosage compensation mechanisms. In general, human lncRNAs impact early development and affect human disease. However, whether lncRNAs represent “byproducts” of transcription or essential biomolecules in gene regulation, e.g. X- inactivation, has been under continuous debate. Experimental models for functional lncRNA and evolution of RNA-mediated mechanisms are scarce. Our research focuses on a cluster of lncRNA genes functional for X-inactivation. This cluster of lncRNA genes have evolved concomitantly on the X chromosome, from ancestral protein-coding genes through pseudogenization and gain of RNA functions, coincidental with the evolution of X-inactivation along the divergence of eutherian and marsupial mammals. Our recent data have demonstrated that, within this gene cluster in the mouse genome, the lncRNA Jpx activates lncRNA Xist and functions as a molecular switch for mouse X-inactivation. We have also reported, by comparing mouse and human homologs, functional conservation of Jpx in X-inactivation despite overall sequence and RNA structural divergence. But questions regarding 1) what sequence variations are determinant of lncRNA function for X-inactivation, 2) are there regulatory features of lncRNA essential for X-inactivation, 3) what drives the function of Xic locus in X- chromosome silencing, are unresolved. These are questions directly related to the evolution of dosage compensation in mammals. In this project, we will (1) determine the regional sequence motifs of Jpx lncRNA that are essential for its function in X-inactivation, (2) determine whether both trans and cis activities of Jpx lncRNA are necessary for its function in X-inactivation, and (3) understand the function of Xic in chromosome silencing and the requirement of its cis and trans activities by integrating the Xic sequence into an autosome. The proposed research is anticipated to uncover insights into the molecular features of lncRNA for function in X-inactivation, which will contribute to our understanding about not only lncRNA evolution, but also dosage compensation evolution in mammals.