N6-methyladenosine (m6A) is the most common messenger RNA and long noncoding RNA modification in eukaryotes. Through its effects on RNA processing, export, translation, and decay, m6A influences diverse processes including stem cell differentiation, energy homeostasis, and spermatogenesis. The cellular functions of m6A are mediated through its recognition by m6A reader proteins. Heterogeneous nuclear ribonucleoprotein G (HNRNPG) is a novel m6A reader protein that functions in neural development and regulates several alternative splicing events linked to neuromuscular diseases. Our preliminary data indicate that m6A influences the cellular localization of HNRNPG, and that m6A and HNRNPG co-regulate the alternative splicing of ~1,000 m6A-containing transcripts. To investigate how m6A regulates HNRNPG localization, I will examine the function of a specific m6A-modified lncRNA in the nuclear retention of HNRNPG, and I will determine the role of nucleo- cytoplasmic shuttling in the cellular function of HNRNPG. To investigate how m6A impacts HNRNPG-regulated alternative splicing events, I will use a pull-down approach to identify splicing factors that are recruited to m6A- modified transcripts by HNRNPG, and I will examine how knockdown of these splicing factors influences alternative splicing. Using the m6A reader HNRNPG as a model, these studies will elucidate novel mechanisms by which m6A influences protein localization and alternative splicing, two crucial cellular processes that are disrupted in a variety of human diseases.

Public Health Relevance

Heterogeneous nuclear ribonucleoprotein G (HNRNPG) recognizes N6-methyladenosine (m6A) modifications in RNA, and m6A in turn influences the cellular localization of HNRNPG and alternative splicing events regulated by HNRNPG. Protein localization and alternative splicing are disrupted in many human diseases, particularly in neurological diseases. By elucidating how m6A impacts protein localization and alternative splicing, this work will enhance our understanding of how these important processes are regulated in the cell, and our ability to manipulate these processes for therapeutic purposes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZRG1)
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Gibbs, Kenneth D
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University of Chicago
Schools of Medicine
United States
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Zhou, Katherine I; Pan, Tao (2016) Structures of the m(6)A Methyltransferase Complex: Two Subunits with Distinct but Coordinated Roles. Mol Cell 63:183-185