title: Involvement of PARP1 in the regulation of alternative splicing.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky , Lexington, KY, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Matveeva
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky , Lexington, KY, USA.
authors.forename: John
authors.initials: J
authors.lastname: Maiorano
authors.affiliation: Department of Molecular Biosciences, Northwestern University , Evanston, IL, USA.
authors.forename: Qingyang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Computer Engineering and Computer Science, University of Louisville , Louisville, KY, USA.
authors.forename: Abdallah M
authors.initials: AM
authors.lastname: Eteleeb
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA; Department of Science, University of Basilicata, Potenza, Italy.
authors.forename: Paolo
authors.identifier: 0000-0001-7250-0678
authors.initials: P
authors.lastname: Convertini
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky , Lexington, KY, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Science, University of Basilicata , Potenza, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: Infantino
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky , Lexington, KY, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stamm
authors.affiliation: Department of Molecular Biosciences, Northwestern University , Evanston, IL, USA.
authors.forename: Jiping
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Computer Engineering and Computer Science, University of Louisville , Louisville, KY, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Rouchka
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky , Lexington, KY, USA.
authors.forename: Yvonne N
authors.initials: YN
authors.lastname: Fondufe-Mittendorf
keywords: Epigenetics; PARP1; chromatin; cotranscriptional splicing; gene regulation