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2 Zefeng Wang Associate Professor Department of Pharmacology University of North Carolina at Chapel Hill USA
3 Biography Prof. Zefeng Wang received his Ph.D. degree from Johns Hopkins Medical School, worked as a Damon Runyon fellow at Massachusetts Institute of Technology before becoming an assistant professor at University of North Carolina at Chapel Hill. Dr. Wang’s research focuses on the regulation of gene expression in RNA level. He has made significant contribution to the filed of RNA biology by developing a series of new methods to study RNA splicing and degradation, and has pioneered the filed of engineering RNA binding proteins. His work was recognized by several research awards.
4 Research Interests Systematic study of the regulation of alternative splicing Mechanisms and functional roles of splicing mis-regulation in cancers Manipulation of RNA processing with artificial protein factors
5 Recent Publications Wang Y, Cheong CG, Hall TM and Wang Z. Engineering splicing factors with designed specificities (2009). Nature Method. 6(11): Epub 2009 Oct 4 Wang Y, Ma M, Xiao XS and Wang Z. Intronic splicing enhancers, cognate splicing factors and context dependent regulation rules. (2012) Nature Structure Molecular Biology, doi: /nsmb Epub Sep 16. Choudhury R, Dominguez D, Wang Y and Wang Z. Engineering RNA endonucleases with customized sequence specificities (2012). Nature Communication 23;3:1147. doi: /ncomms2154. Wang Y, Xiao X, Zhang J, Choudhury R, Robertson A, Li K, Ma M, Burge CB, Wang Z. A complex network of factors with overlapping affinities represses splicing through intronic elements. (2013) Nat Struct Mol Biol. 20(1): doi: /nsmb PMCID: PMC Zhang W, Wang Y, Dong S, Choudhury R, Jin Y and Wang Z Treatment of type 1 Myotonic Dystrophy by engineering site-specific RNA endonucleases that target (CUG)n repeats. (2013) Molecular Therapy. Oct 23 doi: /mt Epub ahead of print Choudhury R, Ghose Roy S, Tsai YS, Tripathy A , Graves LM and Wang Z. The splicing activator DAZAP1 integrates splicing control into MEK/Erk regulated cell proliferation and migration. Nature Communications (2014) Jan 23;5:3078. doi: /ncomms4078 Matera AG* and Wang Z* (co-corresponding author). Ribonucleoprotein assembly and dynamics: A day in the life of the spliceosome. Nature Review Molecular Cell Biology (2014) Jan 23;15(2): doi: /nrm3742 Tsai YS, Gomez SM, and Wang Z. Prevalent RNA recognition motif duplication in the human genome. RNA (2014) May;20(5): doi: /rna Epub 2014 Mar 25 Wang Y, Chen D, Qian H, Tsai YS, Shao S, Dominguez D and Wang Z. The splicing factor RBM4 controls apoptosis, proliferation, and migration to suppress tumor progression. Cancer Cell (2014) Sep 8; 26(3): doi: /j.ccr
6 Systematic Identification of Intronic Splicing Silencers with FAS-ISSgroups A CTCCTC / CGCATC\ B TACAGCT / TACGGCT C CTTCAG / CGTCAC D GAACAG / GTACCG E CAAAGGA /CATACGA F AGATATT / AGCTGTT G ACATGA / ACGTGA H AATTTA / AGTGTC I AGTAGG / AGCAGT U CACACCA /CATAGCA Representative k-mers/mutations Random 10mer G Hyg FP Stable transfection GFP Normal splicing Exon skipping due to ISS Red Fluorescence Green Fluorescence Sort and clone green cells, recover ISS insertion Yang Wang et al, NSMB 2013
7 Identify intronic splicing enhancers by FAS-ISEDissimilarity ISE group Representative 6-mer A GGGTTT B GGTGGT C TTTGGG D GAGGGG E GGTATT F GTAACG Random region Weak intron G FP Exon1 Exon3 Stable transfection Unspliced mRNA GFP mRNA FACS sorting Cloning PCR & Sequencing ISE sequences 117 ISE decamers, 109 unique All ISE function as ESS (i.e., inhibit splicing) when inserted in exons Wang Y et al, 2012 NSMB
8 An Overlapping Network of trans-factors Recognize ISSs and ISEsH A G B C U GAACAG CUUCAG CAAAGGA ACAUGA CACACCA UACAGCU AGAUAUU CUCCUC AGUAGG AAUUUA PTB YB-1 hnRNP UL hnRNP A2 hnRNP A3 GRSF-1 SFRS1 hnRNP H1 hnRNP F hnRNP D hnRNP DL RBM45 G3BP1 G3BP2 DAZAP1 CIRBP hnRNP L hnRNP A0 SFPQ hnRNP Q KHSRP hnRNP A1 Nono nPTB A complex connectivity map => regulatory plasticity B F C A hnRNP H2 hnRNP D SFPQ SmB FUS TIA1 hnRNP M ZCCHC8 GRSF1 CNBP RBM4 hnRNP H DAZAP1 DHX36 hnRNP F ZRANB1/2 D E U1A GGGTTT GGTGGT TTTGGG GAGGGG GGTATT GTAACG Factors involved in tumor patheogenesis Wang Y et. al, Nat Struc & Mol Bio 2012 Wang Y et. al, Nat Struc & Mol Bio 2013
9 DAZAP1 integrates splicing control into MEK/Erk regulated cell proliferation and migrationExternal cues MEK ERK1/2 DAZAP1 DAZAP1 DAZAP1 hnRNPA1 1 2 DAZAP1 Regulating splicing of >300 genes; Control cell growth & proliferation Chundhury et, al Nature Communications
10 RBM4-mediated splicing regulation balance controls cell growth/proliferationBcl-xL Bcl-xS Pro-apoptotic Anti-apoptotic RBM4 SRSF1 cancer-related AS (BIN1, RON, S6k1...) cancer-related AS (CD44, TEAD4 ...) S6K P 4EBP1 Cell proliferation & translation mTOR Wang Y et. al, Cancer Cell, 2014
11 Engineered splicing factors: Restore normal splicing in cancerSplicing inhibition by PUF-Gly Splicing activation by PUF-RS Gly-rich domain RS domain Artificial site-specific RNA endonuclease: Cleave toxic RNA Gene silencing in mitochondrion & chloroplast PIN 3’ 5’ Wang Y et al, 2009 Nature Methods Chundhury et al, 2012, Nature Communications
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