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

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.

PARP1 restricts Epstein Barr Virus lytic reactivation by binding the BZLF1 promoter

“…CTCF has emerged as an important cofactor of the host protein PARP1 (Farrar et al, 2011; Ong et al, 2013; Nalabothula et al, 2015; Zhao et al, 2015). We hypothesized that PARP1 and CTCF may cooperate at the BZLF1 promoter to collectively restrict EBV lytic reactivation.…”

“…Recent work in the PARP field has revealed new functions for PARP1 beyond its enzymatic activity (Zhao et al, 2015; Nalabothula et al, 2015). We hypothesized that in the context of EBV lytic reactivation, PARP1 binding may be more relevant than its activity.…”

PARP mediated chromatin unfolding is coupled to long-range enhancer activation

“…Though PARP1 is usually studied in the context of DNA damage sensing and repair, it has also been associated with the regulation of gene expression (Ogino et al, 2007) and with active chromatin and regions with regulatory potential as assayed by DNase I hypersensitivity (Nalabothula et al, 2015). More specifically, PARP and Parp1-dependent PARylation have been implicated in gene regulation from distal enhancer elements that are controlled by nuclear hormone receptors including; ecdysone inducible puffs in Drosophila (Sawatsubashi et al, 2004) and the action of the liganded progesterone receptor in mammalian breast cancer cells (Wright et al, 2012).…”

Epigenetic and redox biomarkers: Novel insights from the MARK-AGE study

“…Furthermore, poly(ADP-ribosyl)ation has been associated with mammalian longevity (Mangerich and Burkle, 2012). Interestingly, genomewide methylation analyses revealed changes in methylation patterns resulting from inhibition of PARylation in breast cancer cell lines, indicating a reciprocal interplay between PARP1 and DNA methylation (Nalabothula et al, 2015). Caiafa and coworkers demonstrated that inhibition of PARylation induces in vivo DNA hypermethylation (de Capoa et al, 1999;Zardo et al, 1997Zardo et al, , 2002 and that CCCTC-binding factor (CTCF) is involved in the cross-talk between poly(ADP-ribosyl) ation and DNA methylation (Guastafierro et al, 2008), suggesting that PAR protects DNA from methylation.…”