Loss of Parp-1 affects gene expression profile in a genome-wide manner in ES cells and liver cells.
BACKGROUND
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. However, the impact of Parp-1-deficiency on the regulation of genome-wide gene expression has not been fully studied yet.


RESULTS
We 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.


CONCLUSIONS
These 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.
Ogino
Hideki
H
ADP-ribosylation in Oncology Project, National Cancer Center Research Institute, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan. hogino@gan2.res.ncc.go.jp <hogino@gan2.res.ncc.go.jp>
Nozaki
Tadashige
T
Gunji
Akemi
A
Maeda
Miho
M
Suzuki
Hiroshi
H
Ohta
Tsutomu
T
Murakami
Yasufumi
Y
Nakagama
Hitoshi
H
Sugimura
Takashi
T
Masutani
Mitsuko
M
D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000378:metabolism*; D020869:Gene Expression Profiling; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases