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

• Published in: PloS one 2015-08, Vol.10 (8), p.e0135410-e0135410
• Main Authors: Nalabothula, Narasimharao, Al-jumaily, Taha, Eteleeb, Abdallah M, Flight, Robert M, Xiaorong, Shao, Moseley, Hunter, Rouchka, Eric C, Fondufe-Mittendorf, Yvonne N
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; Architectural engineering; Binding; Biochemistry; Breast cancer; Chromatin; Chromatin - genetics; Chromatin Assembly and Disassembly - genetics; Chromatin remodeling; Computer engineering; Computer science; Deoxyribonuclease; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA methylation; DNA Methylation - genetics; DNA repair; Gene expression; Gene regulation; Genome, Human; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Humans; MCF-7 Cells; Nucleosomes; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - genetics; Promoter Regions, Genetic; Proteins; Recombination; Regulatory sequences; Regulatory Sequences, Nucleic Acid - genetics; Repair; Ribose; RNA polymerase; Splicing; Studies; Transcription; Transcription, Genetic; Tumor cell lines
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0135410

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.