N6-methyl-adenosine (m6A) is the most abundant internal modifications in messenger and long non- coding RNA. This modification occurs in many sites of mRNA with proposed functions including splicing, export, cytoplamic localization, stability, translation activity, and immune tolerance. Functional inquiries of the m6A modification have been revived since 2011 due to our discovery of human enzymes that reverse m6A methylation and transcriptome-wide mapping of m6A patterns in mRNA and non-coding RNA by others. Together, these results strongly indicate that m6A is a highly dynamic RNA modification that plays important regulatory roles. Recent studies from our laboratories indicate that m6A modifications exert their function through their interactions with specific cellular proteins termed m6A-readers. This proposal investigates biological functions of m6A-reader proteins and addresses the underlying molecular and cellular mechanisms. We have identified several m6A-selective binding proteins, and our preliminary data indicate that these proteins significantly impact RNA localization and affect mRNA stability and splicing. Our proposed research will establish specific, molecular models of m6A recognition and cellular function and mechanism of two families of human m6A-reader proteins.
Aim 1 will investigate the molecular and cellular mechanisms of a cytoplasmic m6A-reader protein that directly recognizes the m6A-methylated mRNA to affect localization and stability of the target mRNA.
Aim 2 will study the molecular mechanism of one nuclear m6A-reader protein. We have discovered an m6A-switch mechanism that involves m6A-induced RNA conformational switch. The m6A-induced structural change enhances binding of mRNA binding proteins to single-stranded RNA motifs that are otherwise embedded in weak secondary structures. 2)
N6-methyl-adenosine (m6A) is a prevalent modification in messenger and long non-coding RNAs that play important roles in the regulation of gene expression. The proposed research will establish function and mechanism of two families of human m6A-reader proteins. Since m6A- readers have already been implicated in cancer, aging, mental retardation and autoimmunity, our studies should have impacts on human health and disease.
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| Shi, Hailing; Zhang, Xuliang; Weng, Yi-Lan et al. (2018) m6A facilitates hippocampus-dependent learning and memory through YTHDF1. Nature 563:249-253 |
| Koranda, Jessica L; Dore, Lou; Shi, Hailing et al. (2018) Mettl14 Is Essential for Epitranscriptomic Regulation of Striatal Function and Learning. Neuron 99:283-292.e5 |
| Lewis, Cole J T; Pan, Tao; Kalsotra, Auinash (2017) RNA modifications and structures cooperate to guide RNA-protein interactions. Nat Rev Mol Cell Biol 18:202-210 |
| Zhou, Katherine I; Liu, Nian; Pan, Tao (2017) Identification of N6-methyladenosine reader proteins. Methods 126:105-111 |
| Shi, Hailing; Wang, Xiao; Lu, Zhike et al. (2017) YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. Cell Res 27:315-328 |
| Liu, Nian; Zhou, Katherine I; Parisien, Marc et al. (2017) N6-methyladenosine alters RNA structure to regulate binding of a low-complexity protein. Nucleic Acids Res 45:6051-6063 |
| Roundtree, Ian A; Luo, Guan-Zheng; Zhang, Zijie et al. (2017) YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs. Elife 6: |
| Evans, Molly E; Clark, Wesley C; Zheng, Guanqun et al. (2017) Determination of tRNA aminoacylation levels by high-throughput sequencing. Nucleic Acids Res 45:e133 |
| Zhao, Boxuan Simen; Wang, Xiao; Beadell, Alana V et al. (2017) m6A-dependent maternal mRNA clearance facilitates zebrafish maternal-to-zygotic transition. Nature 542:475-478 |
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