Identification of Egr1 Direct Target Genes in the Uterus by In Silico Analyses with Expression Profiles from mRNA Microarray Data
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Early growth response 1 (Egr1) is a zinc-finger transcription factor to direct second-wave gene expression leading to cell growth, differentiation and/or apoptosis. While it is well-known that Egr1 controls transcription of an array of targets in various cell types, downstream target gene(s) whose transcription is regulated by Egr1 in the uterus has not been identified yet. Thus, we have tried to identify a list of potential target genes of Egr1 in the uterus by performing multi-step in silico promoter analyses. Analyses of mRNA microarray data provided a cohort of genes (102 genes) which were differentially expressed (DEGs) in the uterus between Egr1(+/+) and Egr1(–/–) mice. In mice, the frequency of putative EGR1 binding sites (EBS) in the promoter of DEGs is significantly higher than that of randomly selected non-DEGs, although it is not correlated with expression levels of DEGs. Furthermore, EBS are considerably enriched within –500 bp of DEG’s promoters. Comparative analyses for EBS of DEGs with the promoters of other species provided power to distinguish DEGs with higher probability as EGR1 direct target genes. Eleven EBS in the promoters of 9 genes among analyzed DEGs are conserved between various species including human. In conclusion, this study provides evidence that analyses of mRNA expression profiles followed by two-step in silico analyses could provide a list of putative Egr1 direct target genes in the uterus where any known direct target genes are yet reported for further functional studies.
Abstract
Early growth response 1 (Egr1) is a zinc-finger transcription factor to direct second-wave gene expression leading to cell growth, differentiation and/or apoptosis. While it is well-known that Egr1 controls transcription of an array of targets in various cell types, downstream target gene(s) whose transcription is regulated by Egr1 in the uterus has not been identified yet. Thus, we have tried to identify a list of potential target genes of Egr1 in the uterus by performing multi-step in silico promoter analyses. Analyses of mRNA microarray data provided a cohort of genes (102 genes) which were differentially expressed (DEGs) in the uterus between Egr1(+/+) and Egr1(–/–) mice. In mice, the frequency of putative EGR1 binding sites (EBS) in the promoter of DEGs is significantly higher than that of randomly selected non-DEGs, although it is not correlated with expression levels of DEGs. Furthermore, EBS are considerably enriched within –500 bp of DEG’s promoters. Comparative analyses for EBS of DEGs with the promoters of other species provided power to distinguish DEGs with higher probability as EGR1 direct target genes. Eleven EBS in the promoters of 9 genes among analyzed DEGs are conserved between various species including human. In conclusion, this study provides evidence that analyses of mRNA expression profiles followed by two-step in silico analyses could provide a list of putative Egr1 direct target genes in the uterus where any known direct target genes are yet reported for further functional studies.
참고문헌 (24)
- Arora S, "Egr1 regulates the coordinated expression of numerous EGF receptor target genes as identified by ChIP-on-chip", Genome Biology, 9, pp.R166~ (2008)
- Baron V, "The transcription factor EGR1 is a direct regulator of multiple tumor suppressors including TGFbeta1, PTEN, p53, and fibronectin", Cancer Gene Therapy, 13, pp.115~124 (2006)
- Calogero A, "Inhibition of cell growth by Egr-1 in human primary cultures from malignant glioma", Cancer Cell International, 4, pp.1~ (2004)
- Cartharius K, "Matinspector and beyond: Promoter analysis based on transcription factor binding sites", Bioinformatics, 21, pp.2933~2942 (2005)
- Chen CC, "Egr-1 is activated by 17beta-estradiol in MCF-7 cells by mitogen-activated protein kinase-dependent phosphorylation of ELK-1", Journal of Cellular Biochemistry, 93, pp.1063~1074 (2004)
- Choi BH, "P21 waf1", cip1 expression by curcumin in U-87MG human glioma cells: Role of Early growth response-1 expression, 2008, pp.68, 1369~1377
- de Mestre AM, "Early growth response gene 1 (Egr1) regulates heparanase gene transcription in tumor cells", The Journal of Biological Chemistry, 280, pp.5136~35147 (2005)
- Duan WR, "GnRH regulates early growth response protein 1 transcription through multiple promoter elements", Molecular Endocrinology, 16, pp.221~233 (2002)
- Ishikawa H, "Early growth response gene-1 plays a pivotal role in down-regulation of a cohort of genes in uterine leiomyoma", Journal of Molecular Endocrinology, 39, pp.333~341 (2007)
- Koldamova R, "Genome-wide approaches reveal Egr1-controlled regulatory networks associated with neurodegeneration", Neurobiology of Disease, 63C, pp.107~114 (2013)
- Lee SL, "Luteinizing hormone deficiency and female infertility in mice lacking the transcription factor NGFI-A (egr-1)", Science, 273, pp.219~1221 (1996)
- Messeguer X, "Promo: Detection of known transcription regulatory elements using species-tailored searches", Bioinformatics, 18, pp.333~334 (2002)
- Milbrandt J, "A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor", Science, 238, pp.797~799 (1987)
- Patwardhan S, "Egr3, a novel member of the Egr family of genes encoding immediate-early transcription factors", Oncogene, 6, pp.917~928 (1991)
- Reiss N, "Mechanism of mitogen-activated protein kinase activation by gonadotropin-releasing hormone in the pituitary of alphat3-1 cell line: Differential roles of calcium and protein kinase C", Endocrinology, 138, pp.673~1682 (1997)
- Saunders BD, "Differential use of signal transduction pathways in the gonadotropin-releasing hormone-mediated regulation of gonadotropin subunit gene expression", Endocrinology, 139, pp.1835~1843 (1998)
- Shin SY, "Egr-1 is necessary for fibroblast growth factor-2-induced transcriptional activation of the glial cell line-derived neurotrophic factor in murine astrocytes", The Journal of Biological Chemistry, 284, pp.30583~30593 (2009)
- Sundaresan S, "Stimulation of mitogen-activated protein kinase by gonadotropin-releasing hormone: Evidence for the involvement of protein kinase C", Endocrinology, 137, pp.04~311 (1996)
- Svaren J, "Egr1 target genes in prostate carcinoma cells identified by microarray analysis", The Journal of Biological Chemistry, 275, pp.38524~38531 (2000)
- Tang C, "Global analysis of in vivo Egr1-binding sites in erythroleukemia cell using chromatin immunoprecipitation and massively parallel sequencing", Electrophoresis, 31, pp.2936~2943 (2010)
- Thiel G, "Regulation of life and death by the zinc finger transcription factor Egr-1", Journal of Cellular Physiology, 193, pp.287~292 (2002)
- Topilko P, "Multiple pituitary and ovarian defects in Krox-24 (NGFI-A, Egr-1)-targeted mice", Molecular Endocrinology, 12, pp.107~122 (1998)
- Virolle T, "Egr1 promotes growth and survival of prostate cancer cells. Identification of novel Egr1 target genes", The Journal of Biological Chemistry, 278, pp.11802~11810 (2003)
- Yoshino M, "Early growth response gene-1 regulates the expression of the rat luteinizing hormone receptor gene", Biology of Reproduction, 66, pp.1813~1819 (2002)