Proper control of gene expression is essential for life. While substantial advances have been made in the discovery of DNA sequences and transcription factors that act combinatorially to regulate transcription, much less is known about later steps in the gene expression program. Nevertheless, it is now clear that substantial regulation of gene expression occurs post-transcriptionally, in pre-mRNA splicing, RNA localization, translation, and RNA decay, and in the coordination of RNAs by RNA binding proteins (RBPs), microRNAs, and RNA chemical modifications. While many sequence motifs are known to mediate post-transcriptional regulation, RNA secondary structures that govern access to these motifs are much less well understood. The long term goal of this project is to enable structural characterization of RNAs on a genome-wide scale. First, we will apply a recently developed method to map secondary structures of most human RNAs in living cells. Second, we will develop methods to follow the fate of RNA secondary structures through the RNA life cycle. Third, we will develop high throughput methods to perturb and test functions of RNA structures. This integrated pipeline of new technologies will enable investigators to identify and decode regulatory RNA elements in the genome with unprecedented speed and accuracy.

Public Health Relevance

The control of gene expression lies at the heart of understanding fundamental biological processes and human diseases. An important level of gene control occurs at the level of how RNA molecules fold up within cells. This project will develop tools to identify RNA shapes in human cells and what they do, providing insights into how changes in RNA shape can lead to health or disease.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
5R01HG004361-08
Application #
9266813
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Pazin, Michael J
Project Start
2007-09-18
Project End
2019-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
8
Fiscal Year
2017
Total Cost
$486,000
Indirect Cost
$137,015
Name
Stanford University
Department
Dermatology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94304
Tong, Jiyu; Cao, Guangchao; Zhang, Ting et al. (2018) m6A mRNA methylation sustains Treg suppressive functions. Cell Res 28:253-256
Chen, Lu; Roake, Caitlin M; Freund, Adam et al. (2018) An Activity Switch in Human Telomerase Based on RNA Conformation and Shaped by TCAB1. Cell 174:218-230.e13
Lu, Zhipeng; Chang, Howard Y (2018) The RNA Base-Pairing Problem and Base-Pairing Solutions. Cold Spring Harb Perspect Biol 10:
Simsek, Deniz; Tiu, Gerald C; Flynn, Ryan A et al. (2017) The Mammalian Ribo-interactome Reveals Ribosome Functional Diversity and Heterogeneity. Cell 169:1051-1065.e18
Bailey, Alexis S; Batista, Pedro J; Gold, Rebecca S et al. (2017) The conserved RNA helicase YTHDC2 regulates the transition from proliferation to differentiation in the germline. Elife 6:
Lu, Zhipeng; Carter, Ava C; Chang, Howard Y (2017) Mechanistic insights in X-chromosome inactivation. Philos Trans R Soc Lond B Biol Sci 372:
Chen, Y Grace; Kim, Myoungjoo V; Chen, Xingqi et al. (2017) Sensing Self and Foreign Circular RNAs by Intron Identity. Mol Cell 67:228-238.e5
Lee, Byron; Flynn, Ryan A; Kadina, Anastasia et al. (2017) Comparison of SHAPE reagents for mapping RNA structures inside living cells. RNA 23:169-174
Li, Hua-Bing; Tong, Jiyu; Zhu, Shu et al. (2017) m6A mRNA methylation controls T cell homeostasis by targeting the IL-7/STAT5/SOCS pathways. Nature 548:338-342
Tan, Justin L; Fogley, Rachel D; Flynn, Ryan A et al. (2016) Stress from Nucleotide Depletion Activates the Transcriptional Regulator HEXIM1 to Suppress Melanoma. Mol Cell 62:34-46

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