N6-methyl-adenosine (m6A) is the most abundant internal modifications in messenger and long non-coding RNA. This modification occurs in many sites in mRNA with functions including splicing, export, localization, stability, translation, and immune response. Functional inquiries of the m6A modification have been intensely studied since 2011 and have become an integral component of the new field of epitranscriptomics. Studies from our laboratories and others indicate that m6A modifications exert their function through interactions with specific cellular proteins termed m6A readers. This proposal investigates the biological function of m6A reader proteins and addresses the underlying molecular and cellular mechanisms. Our proposed research will establish molecular models of m6A function in cells through two nuclear-localized m6A reader proteins and their mechanisms of action.
Aim 1 will investigate the molecular and cellular mechanisms of co-transcriptional, m6A-dependent regulation of mRNA alternative splicing. We will test our model on HNRNPG/m6A-dependent control through RNA polymerase II pausing and the effect of nascent RNA structure using targeted approaches.
Aim 2 will study the function and mechanism of HNRNPG assembly through a low-complexity region and the effect of assembly on interacting with m6A-modified RNA and alternative splicing. We will test a molecular model on these aspects using biochemical and cellular approaches.
Aim 3 will study the m6A-dependent mechanism of two nuclear-localized m6A reader proteins that regulate transcriptome-wide alternative splicing. We will elucidate the interplay among these two proteins on specific exon targets and how this occurs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM113194-05
Application #
9816451
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Bender, Michael T
Project Start
2015-09-01
Project End
2023-06-30
Budget Start
2019-08-12
Budget End
2020-06-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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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
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
Hsu, Phillip J; Zhu, Yunfei; Ma, Honghui et al. (2017) Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res 27:1115-1127

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