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mRNA Methylation: a Novel Regulatory Mechanism in the Neuronal Transcriptome

项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

ARGUELLO, ALEXANDER

项目受资助机构

DUKE UNIVERSITY

项目编号

5R00MH104712-05

立项年度

2018

立项时间

未公开

研究期限

未知 / 未知

项目级别

国家级

受资助金额

249000.00美元

学科

Genetics;Mental Health;Neurosciences

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

MEYER, KATHRYN D

参与机构

NATIONAL INSTITUTE OF MENTAL HEALTH

项目标书摘要：DESCRIPTION (provided by applicant): This project is designed to enhance the skills, knowledge, and scientific training of Dr. Kate Meyer as she transitions into a career as an independent research scientist. Dr. Meyer recently published a landmark study in which she showed for the first time that N6-methyladenosine (m6A) is a widespread, reversible base modification in mRNA. m6A exhibits a unique distribution within mRNAs, with the most highly enriched regions being near the stop codon and in the 5'UTR. Additionally, Dr. Meyer discovered that m6A is particularly abundant within the brain and that its levels increase steadily throughout neurodevelopment. This suggests that mRNA methylation is a widespread mechanism of neuronal mRNA regulation which contributes to brain development and function. However, despite the prevalence of m6A within the brain and its potential to influence a substantial portion of the neuronal transcriptome, its function remains unknown. The research proposed here will utilize a combination of technically and conceptually innovative approaches to investigate the localization, regulation, and function of m6A in neuronal mRNAs. In Aim 1, Dr. Meyer will develop a new tool for globally detecting m6A residues at single-nucleotide resolution and will identify the neuronal mRNAs which are dynamically methylated during brain development. Aim 2 will utilize a combination of biochemical experiments and m6A mapping techniques to determine the factors that control m6A localization in neuronal mRNAs. These experiments will help answer the long-standing question of how adenosine methylation is directed to particular regions of a transcript. Finally, Aim 3 will explore the role of m6A in regulating neuronal mRNA translation. The results of these experiments will provide important insight into how m6A contributes to basic brain function and will propel our understanding of the molecular and epigenetic events that contribute to mental health and disease. To achieve these research goals, Dr. Meyer will receive extensive training in computer programming and bioinformatic analysis. This new skill set will be invaluable for Dr. Meyer to have, since many of her studies as an independent researcher in the field of molecular neurobiology will involve the generation and analysis of large next- generation sequencing datasets. In addition to enabling Dr. Meyer to develop expertise in computational analysis, this award will further enhance her skills in grant writing, mentoring, and other key areas which are crucial for a successful career as an independent research scientist. Thus, by the end of the mentored phase of this award, Dr. Meyer will be in an ideal position to achieve her long-term career goal of running a successful research laboratory studying mRNA methylation and its role in mental health and disease.

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  • 1.DART-seq: an antibody-free method for global m(6)A detection

    • 关键词：
    • SINGLE-NUCLEOTIDE-RESOLUTION; MESSENGER-RNA METHYLATION; REVEALS;SEQUENCES; WRITERS; M6A
    • Meyer, Kate D.
    • 《NATURE METHODS》
    • 2019年
    • 16卷
    • 12期
    • 期刊

    N-6-methyladenosine (m(6)A) is a widespread RNA modification that influences nearly every aspect of the messenger RNA life-cycle. Our understanding of m(6)A has been facilitated by the development of global m(6)A mapping methods, which use antibodies to immunoprecipitate methylated RNA. However, these methods have several limitations, including high input RNA requirements and cross-reactivity to other RNA modifications. Here, we present DART-seq (deamination adjacent to RNA modification targets), an antibody-free method for detecting m(6)A sites. In DART-seq, the cytidine deaminase APOBEC1 is fused to the m(6)A-binding YTH domain. APOBEC1-YTH expression in cells induces C-to-U deamination at sites adjacent to m(6)A residues, which are detected using standard RNA-seq. DART-seq identifies thousands of m(6)A sites in cells from as little as 10 ng of total RNA and can detect m(6)A accumulation in cells over time. Additionally, we use long-read DART-seq to gain insights into m(6)A distribution along the length of individual transcripts.

    ...

  • 2.The epitranscriptome and synaptic plasticity

    • 关键词：
    • MESSENGER-RNA METHYLATION; FRAGILE-X-SYNDROME; LOCAL PROTEIN-SYNTHESIS;FAT MASS; M(6)A RNA; GENE FTO; OBESITY; N-6-METHYLADENOSINE;TRANSLATION; MEMORY
    • Flamand, Mathieu N.;Meyer, Kate D.
    • 《CURRENT OPINION IN NEUROBIOLOGY》
    • 2019年
    • 59卷
    • 期刊

    RNA modifications, collectively referred to as 'the epitranscriptome,' have recently emerged as a pervasive feature of cellular mRNAs which have diverse impacts on gene expression. In the last several years, technological advances improving our ability to identify mRNA modifications, coupled with the discovery of proteins that add and remove these marks, have substantially expanded our knowledge of how the epitranscriptome shapes gene expression. Efforts to uncover functional roles for mRNA modifications have begun to reveal important roles for some marks within the nervous system, and animal models have emerged which demonstrate severe neurodevelopmental and neurocognitive abnormalities resulting from the loss of mRNA modification machinery. Here, we review the recent advances in the field of neuroepitranscriptomics, with a particular emphasis on how modifications to mRNAs within the brain contribute to synaptic activity.

    ...

  • 4.A potentially abundant junctional RNA motif stabilized by m(6)A and Mg2+

    • 关键词：
    • MESSENGER-RNA; YTH DOMAIN; NUCLEAR-RNA; N-6-METHYLADENOSINE;METHYLATION; TRANSLATION; REVEALS; BINDING; N6-METHYLADENOSINE;METHYLTRANSFERASE
    • Liu, Bei;Merriman, Dawn K.;Choi, Seung H.;Schumacher, Maria A.;Plangger, Raphael;Kreutz, Christoph;Horner, Stacy M.;Meyer, Kate D.;Al-Hashimi, Hashim M.
    • 《NATURE COMMUNICATIONS》
    • 2018年
    • 9卷
    • 期刊

    N-6-Methyladenosine (m(6)A) is an abundant post-transcriptional RNA modification that influences multiple aspects of gene expression. In addition to recruiting proteins, m(6)A can modulate RNA function by destabilizing base pairing. Here, we show that when neighbored by a 5' bulge, m(6)A stabilizes m(6)A-U base pairs, and global RNA structure by similar to 1 kcal mol(-1). The bulge most likely provides the flexibility needed to allow optimal stacking between the methyl group and 3' neighbor through a conformation that is stabilized by Mg2+. A bias toward this motif can help explain the global impact of methylation on RNA structure in transcriptome-wide studies. While m(6)A embedded in duplex RNA is poorly recognized by the YTH domain reader protein and m(6)A antibodies, both readily recognize m(6)A in this newly identified motif. The results uncover potentially abundant and functional m(6)A motifs that can modulate the epitranscriptomic structure landscape with important implications for the interpretation of transcriptome-wide data.

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