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.
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.
|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|
|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|
|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|
|Akerman, Martin; Fregoso, Oliver I; Das, Shipra et al. (2015) Differential connectivity of splicing activators and repressors to the human spliceosome. Genome Biol 16:119|
|Krainer, Adrian R (2015) Splicing: still so much to learn. RNA 21:500-1|
|Hua, Yimin; Liu, Ying Hsiu; Sahashi, Kentaro et al. (2015) Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models. Genes Dev 29:288-97|
|Paz, Sean; Krainer, Adrian R; Caputi, Massimo (2014) HIV-1 transcription is regulated by splicing factor SRSF1. Nucleic Acids Res 42:13812-23|
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