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Control of gene silencing by long noncoding RNAs in trophoblast stem cells

滋养层干细胞中长非编码RNA对基因沉默的控制

基本信息

批准号：
10226855
负责人：
Aki Keean Braceros
金额：
$ 3.79万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
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：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10226855
关键词：
3-Dimensional Address Alleles Architecture Base Pairing Binding Biological Process Cellular biology Chromatin Code Complex Congenital Abnormality CpG Islands DNA DNA Binding DNA-Binding Proteins Data Development Developmental Gene Elements Embryo Embryonic Development Enzymes Epigenetic Process Evaluation Event Fellowship Female Fertilization in Vitro Fluorescent in Situ Hybridization Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Genetic Transcription Genome Genomic Segment Genomics Goals Hi-C Infertility Institution Knowledge Lead Mammals Maps Methods Modeling Molecular Molecular Conformation Mus Play Polycomb Procedures Proteins RNA Interference RNA Sequences Research Research Personnel Role Series Site Specificity Testing Therapeutic Training Training Activity Untranslated RNA Variant Work Writing X Chromosome base blastocyst capture hybridization analysis of RNA targets career design dosage embryonic stem cell epigenetic silencing in utero insight oral communication prevent recruit skills targeted treatment transcription factor transcriptome trophoblast trophoblast stem cell

项目摘要

ABSTRACT Long noncoding RNAs (lncRNAs) make up a large portion of mammalian transcriptomes and have essential roles in diverse biological processes, including silencing of protein-coding genes during early development. In the trophoblast, lncRNAs have been shown to have augmented silencing potency through their relationship with highly conserved chromatin-modifying enzymes called Polycomb Repressive Complexes (PRCs). Specifically, the lncRNAs Xist, Airn, and Kcnq1ot1 direct PRCs to separate genomic domains that each span millions of base pairs, in which specific genes are silenced. Indeed, defective silencing by lncRNAs in the trophoblast leads to inappropriate expression of genes that can be a major cause of infertility, whereby the preimplantation embryo depends on the trophoblast for proper development. Despite the importance of the trophoblast in early embryogenesis, the molecular mechanisms that sustain it, particularly through regulation of gene networks by lncRNA silencing, are unknown. Recent work from our lab has shown that, in trophoblast stem cells (TSCs), the genomic domains silenced by Xist, Airn, and Kcnq1ot1 harbor PRCs that are distributed non-uniformly, with certain regions subject to greater levels of silencing than others. While the underlying features that establish this non-uniformity are not fully known, we and others have proposed that chromatin-associated factors are at least partly responsible. In our recent study, three-dimensional (3D) genome architecture and specific CpG island (CGI) DNA elements appeared to be important contributors. Thus, using TSCs as an ex vivo model for the trophoblast, I propose to investigate how chromatin conformation, contacts between chromatin and lncRNAs, and sequence-specific transcription factors bound to CGIs cooperate to dictate both regional and long-distance silencing in lncRNA-silenced domains. My studies will highlight specific factors that regulate epigenetic networks that sustain the trophoblast. Furthermore, my work will provide new paradigms for gene regulation by lncRNAs, whereby specific DNA-binding proteins control the intensity of silencing induced by lncRNAs on a region-by- region basis. In turn, these data may provide new insights on how to treat birth defects or prevent the infertility that results from altered dosage of lncRNA-silenced genes. My long-term goal is to pursue a career in chromatin and epigenetics research as a principle investigator at a major research institution. The training activities I propose are designed to prepare me for this goal, with the next immediate step to obtain a postdoctoral fellowship in chromatin and epigenetics. To these ends, my research plan will provide me with invaluable training in quantitative genomics and the skills needed to develop and rigorously test hypotheses via computational and molecular cell biology. I have enlisted the help of a collaborator and a co-sponsor whose computational expertise is complementary to that of my primary sponsor. My technical training will be accompanied by professional development in oral communication, scientific writing and evaluation, and networking, which will be instrumental to attaining my goal of becoming an independent investigator.

摘要