Abstract
BackgroundMany lines of evidence suggest that poly(ADP-ribose) polymerase-1 (Parp-1) is involved in transcriptional regulation of various genes as a coactivator or a corepressor by modulating chromatin structure. However, the impact of Parp-1-deficiency on the regulation of genome-wide gene expression has not been fully studied yet.ResultsWe employed a microarray analysis covering 12,488 genes and ESTs using mouse Parp-1-deficient (Parp-1-/-) embryonic stem (ES) cell lines and the livers of Parp-1-/- mice and their wild-type (Parp-1+/+) counterparts. Here, we demonstrate that of the 9,907 genes analyzed, in Parp-1-/- ES cells, 9.6% showed altered gene expression. Of these, 6.3% and 3.3% of the genes were down- or up-regulated by 2-fold or greater, respectively, compared with Parp-1+/+ ES cells (p < 0.05). In the livers of Parp-1-/- mice, of the 12,353 genes that were analyzed, 2.0% or 1.3% were down- and up-regulated, respectively (p < 0.05). Notably, the number of down-regulated genes was higher in both ES cells and livers, than that of the up-regulated genes. The genes that showed altered expression in ES cells or in the livers are ascribed to various cellular processes, including metabolism, signal transduction, cell cycle control and transcription. We also observed expression of the genes involved in the pathway of extraembryonic tissue development is augmented in Parp-1-/- ES cells, including H19. After withdrawal of leukemia inhibitory factor, expression of H19 as well as other trophoblast marker genes were further up-regulated in Parp-1-/- ES cells compared to Parp-1+/+ ES cells.ConclusionThese results suggest that Parp-1 is required to maintain transcriptional regulation of a wide variety of genes on a genome-wide scale. The gene expression profiles in Parp-1-deficient cells may be useful to delineate the functional role of Parp-1 in epigenetic regulation of the genomes involved in various biological phenomena.
Highlights
Many lines of evidence suggest that poly(ADP-ribose) polymerase-1 (Parp-1) is involved in transcriptional regulation of various genes as a coactivator or a corepressor by modulating chromatin structure
Because we previously reported induction of trophoblast lineage in untreated Parp-1-/- embryonic stem (ES) cells during in vitro culture, we speculated that a higher level of H19 expression in Parp-1-/- ES cells may be involved in induction of extraembryonic tissues including trophoblast lineage
During differentiation of ES cells after withdrawal of leukemia inhibitory factor (LIF), expression of H19 as well as other trophoblast marker genes were further up-regulated in Parp-1-/- ES cells compared to Parp-1+/+ ES cells (Fig. 4B)
Summary
Many lines of evidence suggest that poly(ADP-ribose) polymerase-1 (Parp-1) is involved in transcriptional regulation of various genes as a coactivator or a corepressor by modulating chromatin structure. As a co-activator, Parp-1 plays a role in the regulation of ligand-induced transactivation of ecdysone receptor [4], and in the transcriptional control of the target genes by AP-2 [5], and by MYB [6]. Parp-1 modulates the activity of the transcription factor NF-κB and the expression of NF-κB-dependent genes, including inducible nitric oxide synthetase (iNOS) [9]. The expression of nearly 1% of the genes, including those involved in cell cycle control and DNA replication was affected in exon 2 disrupted Parp-1-/- mouse embryonic fibroblasts (EF cells) [10]. Parp-deficient Drosophila showed attenuation of gene expression located in puff loci and lost puff formation, suggesting a role for Parp in the induction of genes located at specific chromosomal loci [11]
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