Abstract

The broad objective of this project is to elucidate key mechanistic and regulatory features of human pre-mRNA splicing, and its functional links to nonsense-mediated mRNA decay. Some of these mechanistic insights will be leveraged to develop targeted antisense oligonucleotide therapeutics, which can be used in the long term for clinical applications in precision medicine. The proposed experiments involve a broad range of experimental and computational approaches, including cell-free and cell-based assays, high-throughput RNA-sequencing and quantitative proteomics, bioinformatics, transgenic mouse models, and antisense pharmacology. The anticipated findings will facilitate therapeutic antisense oligonucleotide design for various diseases, besides expanding our fundamental knowledge of basic post-transcriptional mechanisms and regulation.

Public Health Relevance

These studies will substantially advance our current understanding of fundamental steps in the post-transcriptional control of gene expression, as well as influence the understanding, diagnosis, and treatment of various genetic diseases associated with defective splicing or nonsense mutations.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37GM042699-27
Application #
9177882
Study Section
Special Emphasis Panel (NSS)
Program Officer
Bender, Michael T
Project Start
1989-07-01
Project End
2022-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
27
Fiscal Year
2017
Total Cost
Indirect Cost

  Institution

Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724

  Publications

Wong, Mandy S; Kinney, Justin B; Krainer, Adrian R (2018) Quantitative Activity Profile and Context Dependence of All Human 5' Splice Sites. Mol Cell 71:1012-1026.e3
Sinha, Rahul; Kim, Young Jin; Nomakuchi, Tomoki et al. (2018) Antisense oligonucleotides correct the familial dysautonomia splicing defect in IKBKAP transgenic mice. Nucleic Acids Res 46:4833-4844
Sheng, Lei; Wan, Bo; Feng, Pengchao et al. (2018) Downregulation of Survivin contributes to cell-cycle arrest during postnatal cardiac development in a severe spinal muscular atrophy mouse model. Hum Mol Genet 27:486-498
Aznarez, Isabel; Nomakuchi, Tomoki T; Tetenbaum-Novatt, Jaclyn et al. (2018) Mechanism of Nonsense-Mediated mRNA Decay Stimulation by Splicing Factor SRSF1. Cell Rep 23:2186-2198
Doktor, Thomas Koed; Hua, Yimin; Andersen, Henriette Skovgaard et al. (2017) RNA-sequencing of a mouse-model of spinal muscular atrophy reveals tissue-wide changes in splicing of U12-dependent introns. Nucleic Acids Res 45:395-416
Wu, Xingxing; Wang, Shu-Huei; Sun, Junjie et al. (2017) A-44G transition in SMN2 intron 6 protects patients with spinal muscular atrophy. Hum Mol Genet 26:2768-2780
Allemand, Eric; Myers, Michael P; Garcia-Bernardo, Jose et al. (2016) A Broad Set of Chromatin Factors Influences Splicing. PLoS Genet 12:e1006318
Nomakuchi, Tomoki T; Rigo, Frank; Aznarez, Isabel et al. (2016) Antisense oligonucleotide-directed inhibition of nonsense-mediated mRNA decay. Nat Biotechnol 34:164-6
Anczuków, Olga; Krainer, Adrian R (2015) The spliceosome, a potential Achilles heel of MYC-driven tumors. Genome Med 7:107
Xiong, Hui Y; Alipanahi, Babak; Lee, Leo J et al. (2015) RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. Science 347:1254806

Showing the most recent 10 out of 27 publications