| Autor: |
Matveeva E; Department of Molecular and Cellular Biochemistry, University of Kentucky , Lexington, KY, USA., Maiorano J; Department of Molecular and Cellular Biochemistry, University of Kentucky , Lexington, KY, USA., Zhang Q; Department of Molecular Biosciences, Northwestern University , Evanston, IL, USA., Eteleeb AM; Department of Computer Engineering and Computer Science, University of Louisville , Louisville, KY, USA., Convertini P; Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA; Department of Science, University of Basilicata, Potenza, Italy., Chen J; Department of Molecular and Cellular Biochemistry, University of Kentucky , Lexington, KY, USA., Infantino V; Department of Science, University of Basilicata , Potenza, Italy., Stamm S; Department of Molecular and Cellular Biochemistry, University of Kentucky , Lexington, KY, USA., Wang J; Department of Molecular Biosciences, Northwestern University , Evanston, IL, USA., Rouchka EC; Department of Computer Engineering and Computer Science, University of Louisville , Louisville, KY, USA., Fondufe-Mittendorf YN; Department of Molecular and Cellular Biochemistry, University of Kentucky , Lexington, KY, USA. |
| Abstrakt: |
Specialized chromatin structures such as nucleosomes with specific histone modifications decorate exons in eukaryotic genomes, suggesting a functional connection between chromatin organization and the regulation of pre-mRNA splicing. Through profiling the functional location of Poly (ADP) ribose polymerase, we observed that it is associated with the nucleosomes at exon/intron boundaries of specific genes, suggestive of a role for this enzyme in alternative splicing. Poly (ADP) ribose polymerase has previously been implicated in the PARylation of splicing factors as well as regulation of the histone modification H3K4me3, a mark critical for co-transcriptional splicing. In light of these studies, we hypothesized that interaction of the chromatin-modifying factor, Poly (ADP) ribose polymerase with nucleosomal structures at exon-intron boundaries, might regulate pre-mRNA splicing. Using genome-wide approaches validated by gene-specific assays, we show that depletion of PARP1 or inhibition of its PARylation activity results in changes in alternative splicing of a specific subset of genes. Furthermore, we observed that PARP1 bound to RNA, splicing factors and chromatin, suggesting that Poly (ADP) ribose polymerase serves as a gene regulatory hub to facilitate co-transcriptional splicing. These studies add another function to the multi-functional protein, Poly (ADP) ribose polymerase, and provide a platform for further investigation of this protein's function in organizing chromatin during gene regulatory processes. |
