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

Nalabothula N, Al-jumaily T, Eteleeb AM, Flight RM, Xiaorong S, Moseley H, Rouchka EC, Fondufe-Mittendorf YN - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

CTCF flanking regions overlap with PARP-1-associated nucleosomes.CTCF binding sites on genome scale were mapped with genome-wide PARP-1 associated regions in breast cancer cells in MCF7 cells (blue) and MDA-MB231 cells (red). We quantified the correlation between PARP1 binding and CTCF binding and showed a Pearson correlation r of about 0.18 (p < 0.05) in both cell types (figshare) [50]).
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pone.0135410.g003: CTCF flanking regions overlap with PARP-1-associated nucleosomes.CTCF binding sites on genome scale were mapped with genome-wide PARP-1 associated regions in breast cancer cells in MCF7 cells (blue) and MDA-MB231 cells (red). We quantified the correlation between PARP1 binding and CTCF binding and showed a Pearson correlation r of about 0.18 (p < 0.05) in both cell types (figshare) [50]).

Mentions: Chromatin organization into distinct functional domains is important for the temporal and spatial gene expression patterns required for proper development in the mammalian genome [65]. One such chromatin organizer is CCCTC-binding factor (CTCF), a sequence-specific transcription factor that binds to its target site and links chromosomal domains [66]. Thus CTCF binding sites relate to gene regulatory regions. Indeed, earlier genome-wide analysis studies identified well-positioned nucleosomes and DNase 1 hypersensitive sites as flanking CTCF-binding sites [67]. Additionally, CTCF directly induces PARP1’s PARylation activity in the absence of DNA damage, suggestive of an interaction between these two proteins in vivo [68]. Thus, to further explore the functional binding of PARP1, we performed a genome-wide characterization of its binding to CTCF binding sites. For this, we measured CTCF binding sites in MCF7 cells [69] and used these to analyze PARP1 binding sites in both cell types. We show that PARP1 binds to the nucleosomes flanking the CTCF binding sites in MCF7 cells with Pearson correlation r = 0.2; p < 0.05 (Fig 3). We next asked if that is true for MDA-MB231 as well. We simulated the CTCF binding sites from MCF7 onto MDA-MB231 cells. This was done with the assumption that CTCF binding sites are on DNA sequences which do not change from cell type to cell type, though mindful of the fact that ~20% of CTCF binding sites are cell-type specific [70]. Results from MDA-MB231 cells (Pearson correlation r = 0.17; p < 0.05) recapitulated the results from MCF7 cells (Fig 3). Since, CTCF PARylation protects certain CTCF regions from DNA methylation, underlining the importance of the cross talk between PARP1, CTCF and DNA methylation in the maintenance of nuclear organization [71]. In line with these studies, we next aimed to determine the relationship of PARP1 binding with DNA methylation status.


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

Nalabothula N, Al-jumaily T, Eteleeb AM, Flight RM, Xiaorong S, Moseley H, Rouchka EC, Fondufe-Mittendorf YN - PLoS ONE (2015)

CTCF flanking regions overlap with PARP-1-associated nucleosomes.CTCF binding sites on genome scale were mapped with genome-wide PARP-1 associated regions in breast cancer cells in MCF7 cells (blue) and MDA-MB231 cells (red). We quantified the correlation between PARP1 binding and CTCF binding and showed a Pearson correlation r of about 0.18 (p < 0.05) in both cell types (figshare) [50]).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4549251&req=5

pone.0135410.g003: CTCF flanking regions overlap with PARP-1-associated nucleosomes.CTCF binding sites on genome scale were mapped with genome-wide PARP-1 associated regions in breast cancer cells in MCF7 cells (blue) and MDA-MB231 cells (red). We quantified the correlation between PARP1 binding and CTCF binding and showed a Pearson correlation r of about 0.18 (p < 0.05) in both cell types (figshare) [50]).
Mentions: Chromatin organization into distinct functional domains is important for the temporal and spatial gene expression patterns required for proper development in the mammalian genome [65]. One such chromatin organizer is CCCTC-binding factor (CTCF), a sequence-specific transcription factor that binds to its target site and links chromosomal domains [66]. Thus CTCF binding sites relate to gene regulatory regions. Indeed, earlier genome-wide analysis studies identified well-positioned nucleosomes and DNase 1 hypersensitive sites as flanking CTCF-binding sites [67]. Additionally, CTCF directly induces PARP1’s PARylation activity in the absence of DNA damage, suggestive of an interaction between these two proteins in vivo [68]. Thus, to further explore the functional binding of PARP1, we performed a genome-wide characterization of its binding to CTCF binding sites. For this, we measured CTCF binding sites in MCF7 cells [69] and used these to analyze PARP1 binding sites in both cell types. We show that PARP1 binds to the nucleosomes flanking the CTCF binding sites in MCF7 cells with Pearson correlation r = 0.2; p < 0.05 (Fig 3). We next asked if that is true for MDA-MB231 as well. We simulated the CTCF binding sites from MCF7 onto MDA-MB231 cells. This was done with the assumption that CTCF binding sites are on DNA sequences which do not change from cell type to cell type, though mindful of the fact that ~20% of CTCF binding sites are cell-type specific [70]. Results from MDA-MB231 cells (Pearson correlation r = 0.17; p < 0.05) recapitulated the results from MCF7 cells (Fig 3). Since, CTCF PARylation protects certain CTCF regions from DNA methylation, underlining the importance of the cross talk between PARP1, CTCF and DNA methylation in the maintenance of nuclear organization [71]. In line with these studies, we next aimed to determine the relationship of PARP1 binding with DNA methylation status.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus