University of Utah School of Medicine, Department of Pediatrics, Division of Neonatology, Salt Lake City, Utah 84132-2202, USA.
Physiol Genomics. 2011 Oct 20;43(20):1160-9. doi: 10.1152/physiolgenomics.00242.2010. Epub 2011 Aug 9.
Intrauterine growth retardation (IUGR) predisposes humans toward hippocampal morbidities, such as impaired learning and memory. Hippocampal dual specificity phosphatase 5 (DUSP5) may be involved in these morbidities because DUSP5 regulates extracellular signal-regulated kinase phosphorylation (Erk). In the rat, IUGR causes postnatal changes in hippocampal gene expression and epigenetic characteristics. However, the impact of IUGR upon hippocampal DUSP5 expression and epigenetic characteristics is not known. We therefore hypothesized that IUGR affects hippocampal 1) DUSP5 expression, DNA CpG methylation, and histone code, and 2) erk1/2 phosphorylation in a well-characterized rat model of IUGR. We found that IUGR significantly decreased DUSP5 expression in the day of life (DOL) 0 and 21 male rat, while decreasing only DUSP5 protein levels in the DOL21 female rat. Fluorescent in situ hybridization and immunohistochemistry analyses localized the changes in DUSP5 mRNA and protein, many of which occurred in the dentate gyrus. IUGR also caused sex-specific differences in DNA CpG methylation and histone code in two sites of the hippocampal DUSP5 gene, a 5'-flanking specificity protein-1 (SP1) site and exon 2. Finally, when IUGR decreased DUSP5 protein levels, Erk phosphorylation increased. We conclude that IUGR affects hippocampal DUSP5 expression and epigenetic characteristics in a sex-specific manner.
宫内发育迟缓（IUGR）使人类易患海马体疾病，如学习和记忆受损。双特异性磷酸酶 5（DUSP5）可能与这些疾病有关，因为 DUSP5 调节细胞外信号调节激酶磷酸化（Erk）。在大鼠中，IUGR 导致海马体基因表达和表观遗传特征的产后变化。然而，IUGR 对海马体 DUSP5 表达和表观遗传特征的影响尚不清楚。因此，我们假设 IUGR 会影响海马体 1）DUSP5 表达、DNA CpG 甲基化和组蛋白密码，以及 2）在 IUGR 的大鼠模型中 erk1/2 磷酸化。我们发现，IUGR 显著降低了 DOL0 和 DOL21 雄性大鼠的 DUSP5 表达，而仅降低了 DOL21 雌性大鼠的 DUSP5 蛋白水平。荧光原位杂交和免疫组织化学分析定位了 DUSP5 mRNA 和蛋白的变化，其中许多发生在齿状回。IUGR 还导致了海马体 DUSP5 基因两个位点的 DNA CpG 甲基化和组蛋白密码的性别特异性差异，这两个位点是 5'侧翼特异性蛋白-1（SP1）位点和外显子 2。最后，当 IUGR 降低 DUSP5 蛋白水平时，Erk 磷酸化增加。我们得出结论，IUGR 以性别特异性的方式影响海马体 DUSP5 的表达和表观遗传特征。
