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.
Document Type
Article
Publication Date
2-16-2016
Digital Object Identifier (DOI)
https://doi.org/10.1038/celldisc.2015.46
Funding Information
This research was supported by NIH grants P20 GM103436 (ECR); 2P20 RR020171, 1RO1ES024478, NSF and IRSF grant (YNF-M).
Related Content
Data analyzed have been deposited in GEO with accession numbers GSE56120 and GSE56073.
Repository Citation
Matveeva, Elena; Maiorano, John; Zhang, Qingyang; Eteleeb, Abdallah M.; Convertini, Paolo; Chen, Jing; Infantino, Vittoria; Stamm, Stefan; Wang, Jiping; Rouchka, Eric C.; and Fondufe-Mittendorf, Yvonne N., "Involvement of PARP1 in the Regulation of Alternative Splicing" (2016). Molecular and Cellular Biochemistry Faculty Publications. 97.
https://uknowledge.uky.edu/biochem_facpub/97
Supplementary Figure S1
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Notes/Citation Information
Published in Cell Discovery, v. 2, article no. 15046, p. 1-19.
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