Limits...
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

PARP-1 is enriched at active epigenetic marks.(A) PARP1 associates with genomic regions containing specific histone modifications. Genomic locations of various histone modifications were mapped on PARP-1 bound regions of the human genome. Solid green, red, blue, orange and black lines represent PARP-1 alignment with H3K4me3, H3K36me3, H3K27ac, H3K27me3, and H3K9me3 modifications in MCF7 and MDA-MB231 cells. (B) PARP1 also binds to DNase hypersensitive sites in both cell types.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4549251&req=5

pone.0135410.g002: PARP-1 is enriched at active epigenetic marks.(A) PARP1 associates with genomic regions containing specific histone modifications. Genomic locations of various histone modifications were mapped on PARP-1 bound regions of the human genome. Solid green, red, blue, orange and black lines represent PARP-1 alignment with H3K4me3, H3K36me3, H3K27ac, H3K27me3, and H3K9me3 modifications in MCF7 and MDA-MB231 cells. (B) PARP1 also binds to DNase hypersensitive sites in both cell types.

Mentions: Gene expression is associated with the presence of different types of histone marks present at the promoters of genes. H3K36me3, H3K4me3, and H3K27ac are considered “active” marks, whereas H3K9me3 and H3K27me3 are considered “repressive” marks [63]. We therefore asked whether the binding of PARP1 correlated with the presence of particular histone marks. ChIP-seq reads of various histone marks were obtained [48] and used to correlate the binding of PARP1 to genomic regions containing these histone marks. Using 2 kb windows around annotated TSSs, we computed the mean signal for each histone PTM and estimated the density of PARP1-bound nucleosomal reads. We found that PARP1 associated with the activating histone PTM H3K4me3, and with the elongating mark H3K36me3 (Fig 2A). On the other hand, PARP1 associated neither with regions containing the activating mark H3K27ac nor with the repressive heterochromatin marks H3K9me3 and H3K27me3. We further quantified the correlation of PARP1 and histone PTMs genome-wide (S1 Table) and observed a moderate positive Pearson correlation with H3K4me3 at TSSs of r = 0.357 (p = 0.4e-16) and r = 0.3447 (p < 0.5e-16) in MCF7 and MDA-MB231 cells respectively. However, PARP1’s correlation with other PTMs varied from no relationship to moderate negative correlation and differed across cell lines (figshare [50]).


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)

PARP-1 is enriched at active epigenetic marks.(A) PARP1 associates with genomic regions containing specific histone modifications. Genomic locations of various histone modifications were mapped on PARP-1 bound regions of the human genome. Solid green, red, blue, orange and black lines represent PARP-1 alignment with H3K4me3, H3K36me3, H3K27ac, H3K27me3, and H3K9me3 modifications in MCF7 and MDA-MB231 cells. (B) PARP1 also binds to DNase hypersensitive sites in both cell types.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0135410.g002: PARP-1 is enriched at active epigenetic marks.(A) PARP1 associates with genomic regions containing specific histone modifications. Genomic locations of various histone modifications were mapped on PARP-1 bound regions of the human genome. Solid green, red, blue, orange and black lines represent PARP-1 alignment with H3K4me3, H3K36me3, H3K27ac, H3K27me3, and H3K9me3 modifications in MCF7 and MDA-MB231 cells. (B) PARP1 also binds to DNase hypersensitive sites in both cell types.
Mentions: Gene expression is associated with the presence of different types of histone marks present at the promoters of genes. H3K36me3, H3K4me3, and H3K27ac are considered “active” marks, whereas H3K9me3 and H3K27me3 are considered “repressive” marks [63]. We therefore asked whether the binding of PARP1 correlated with the presence of particular histone marks. ChIP-seq reads of various histone marks were obtained [48] and used to correlate the binding of PARP1 to genomic regions containing these histone marks. Using 2 kb windows around annotated TSSs, we computed the mean signal for each histone PTM and estimated the density of PARP1-bound nucleosomal reads. We found that PARP1 associated with the activating histone PTM H3K4me3, and with the elongating mark H3K36me3 (Fig 2A). On the other hand, PARP1 associated neither with regions containing the activating mark H3K27ac nor with the repressive heterochromatin marks H3K9me3 and H3K27me3. We further quantified the correlation of PARP1 and histone PTMs genome-wide (S1 Table) and observed a moderate positive Pearson correlation with H3K4me3 at TSSs of r = 0.357 (p = 0.4e-16) and r = 0.3447 (p < 0.5e-16) in MCF7 and MDA-MB231 cells respectively. However, PARP1’s correlation with other PTMs varied from no relationship to moderate negative correlation and differed across cell lines (figshare [50]).

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