TY - JOUR
T1 - Sudemycin e influences alternative splicing and changes chromatin modifications
AU - Convertini, Paolo
AU - Shen, Manli
AU - Potter, Philip M.
AU - Palacios, Gustavo
AU - Lagisetti, Chandraiah
AU - De La Grange, Pierre
AU - Horbinski, Craig
AU - Fondufe-Mittendorf, Yvonne N.
AU - Webb, Thomas R.
AU - Stamm, Stefan
N1 - Funding Information:
Funding for open access charge: NIH [CA140474, GM083187 and 5P20RR020171-08]; Cancer Center Core [CA21765]; American Lebanese Syrian Associated Charities (ALSAC) and St. Jude Children’s Research Hospital (SJCRH).
PY - 2014/4
Y1 - 2014/4
N2 - Sudemycin E is an analog of the pre-messenger RNA splicing modulator FR901464 and its derivative spliceostatin A. Sudemycin E causes the death of cancer cells through an unknown mechanism. We found that similar to spliceostatin A, sudemycin E binds to the U2 small nuclear ribonucleoprotein (snRNP) component SF3B1. Native chromatin immunoprecipitations showed that U2 snRNPs physically interact with nucleosomes. Sudemycin E induces a dissociation of the U2 snRNPs and decreases their interaction with nucleosomes. To determine the effect on gene expression, we performed genome-wide array analysis. Sudemycin E first causes a rapid change in alternative pre-messenger RNA splicing, which is later followed by changes in overall gene expression and arrest in the G2 phase of the cell cycle. The changes in alternative exon usage correlate with a loss of the H3K36me3 modification in chromatin encoding these exons. We propose that sudemycin E interferes with the ability of U2 snRNP to maintain an H3K36me3 modification in actively transcribed genes. Thus, in addition to the reversible changes in alternative splicing, sudemycin E causes changes in chromatin modifications that result in chromatin condensation, which is a likely contributing factor to cancer cell death.
AB - Sudemycin E is an analog of the pre-messenger RNA splicing modulator FR901464 and its derivative spliceostatin A. Sudemycin E causes the death of cancer cells through an unknown mechanism. We found that similar to spliceostatin A, sudemycin E binds to the U2 small nuclear ribonucleoprotein (snRNP) component SF3B1. Native chromatin immunoprecipitations showed that U2 snRNPs physically interact with nucleosomes. Sudemycin E induces a dissociation of the U2 snRNPs and decreases their interaction with nucleosomes. To determine the effect on gene expression, we performed genome-wide array analysis. Sudemycin E first causes a rapid change in alternative pre-messenger RNA splicing, which is later followed by changes in overall gene expression and arrest in the G2 phase of the cell cycle. The changes in alternative exon usage correlate with a loss of the H3K36me3 modification in chromatin encoding these exons. We propose that sudemycin E interferes with the ability of U2 snRNP to maintain an H3K36me3 modification in actively transcribed genes. Thus, in addition to the reversible changes in alternative splicing, sudemycin E causes changes in chromatin modifications that result in chromatin condensation, which is a likely contributing factor to cancer cell death.
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U2 - 10.1093/nar/gku151
DO - 10.1093/nar/gku151
M3 - Article
C2 - 24623796
AN - SCOPUS:84899838206
SN - 0305-1048
VL - 42
SP - 4947
EP - 4961
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 8
ER -
