Genome-Wide Profiling of PARP1 Reveals an Interplay with Gene Regulatory Regions and DNA Methylation

Authors

Narasimharao Nalabothula, University of KentuckyFollow
Taha Al-Jumaily, University of KentuckyFollow
Abdallah M. Eteleeb, University of Louisville
Robert M. Flight, University of KentuckyFollow
Shao Xiaorong, University of California - Berkeley
Hunter Moseley, University of KentuckyFollow
Eric C. Rouchka, University of Louisville
Yvonne N. Fondufe-Mittendorf, University of KentuckyFollow

Abstract

Poly (ADP-ribose) polymerase-1 (PARP1) is a nuclear enzyme involved in DNA repair, chromatin remodeling and gene expression. PARP1 interactions with chromatin architectural multi-protein complexes (i.e. nucleosomes) alter chromatin structure resulting in changes in gene expression. Chromatin structure impacts gene regulatory processes including transcription, splicing, DNA repair, replication and recombination. It is important to delineate whether PARP1 randomly associates with nucleosomes or is present at specific nucleosome regions throughout the cell genome. We performed genome-wide association studies in breast cancer cell lines to address these questions. Our studies show that PARP1 associates with epigenetic regulatory elements genome-wide, such as active histone marks, CTCF and DNase hypersensitive sites. Additionally, the binding of PARP1 to chromatin genome-wide is mutually exclusive with DNA methylation pattern suggesting a functional interplay between PARP1 and DNA methylation. Indeed, inhibition of PARylation results in genome-wide changes in DNA methylation patterns. Our results suggest that PARP1 controls the fidelity of gene transcription and marks actively transcribed gene regions by selectively binding to transcriptionally active chromatin. These studies provide a platform for developing our understanding of PARP1's role in gene regulation.

Document Type

Article

Publication Date

8-25-2015

Notes/Citation Information

Published in PLOS One, v. 10, no. 8, article e0135410, p. 1-22.

© 2015 Nalabothula et al.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Digital Object Identifier (DOI)

http://dx.doi.org/10.1371/journal.pone.0135410

Funding Information

This research was supported by NIH grants P20GM103436 (ECR); 2P20 RR020171 (YNF-M) (from the National Center for Research Resources), 1R01ES024478, NSF1517986 and International Rett Syndrome Foundation grant (YNF-M). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Repository Citation

Nalabothula, Narasimharao; Al-Jumaily, Taha; Eteleeb, Abdallah M.; Flight, Robert M.; Xiaorong, Shao; Moseley, Hunter; Rouchka, Eric C.; and Fondufe-Mittendorf, Yvonne N., "Genome-Wide Profiling of PARP1 Reveals an Interplay with Gene Regulatory Regions and DNA Methylation" (2015). Molecular and Cellular Biochemistry Faculty Publications. 77.
https://uknowledge.uky.edu/biochem_facpub/77