Fu Qi, McKnight Robert A, Yu Xing, Callaway Christopher W, Lane Robert H
University of Utah School of Medicine, Department of Pediatrics, Division of Neonatology, P.O. Box 581289, Salt Lake City, UT 84158, USA.
FASEB J. 2006 Oct;20(12):2127-9. doi: 10.1096/fj.06-6179fje. Epub 2006 Aug 29.
Uteroplacental insufficiency leads to intrauterine growth retardation (IUGR) and adult onset insulin resistance in both humans and rats. IUGR rat liver is characterized by persistent changes in histone 3 lysine 9 and lysine 14 acetylation, which may induce postnatal changes in gene expression. We hypothesized that it would be possible to identify hepatic genes whose epigenetic characteristics and mRNA levels are altered due to IUGR using chromatin immunoprecipitation (ChIP) coupled with random primed differential display polymerase chain reaction (PCR). One of the isolated sequences identified contained exon 2 of the dual specificity phosphatase-5 gene (DUSP5). IUGR affected hepatic DUSP5 mRNA levels and exon 2 DNA methylation into adulthood in the rat. DUSP5 dephosphorylates Erk1 and Erk2 within the MAPK signaling cascade, which in turn affects serine 612 phosphorylation of insulin receptor substrate-1 (p612 IRS-1). In adult rat liver, IUGR increased Erk1/Erk2 phosphorylation and p612 IRS-1 phosphorylation. Increased serine phosphorylation of hepatic IRS-1 may contribute to the insulin resistance that characterizes these animals. We conclude that intrauterine growth retardation induced by uteroplacental insufficiency 1) affects the hepatic epigenetic characteristics and mRNA of the DUSP-5 and 2) increases hepatic insulin receptor substrate-1 phosphorylation at serine 612 in adult rats.
子宫胎盘功能不全可导致人类和大鼠出现宫内生长迟缓（IUGR）及成年期胰岛素抵抗。IUGR大鼠肝脏的特征是组蛋白3赖氨酸9和赖氨酸14乙酰化持续改变，这可能会诱导出生后基因表达的变化。我们推测，利用染色质免疫沉淀（ChIP）结合随机引物差异显示聚合酶链反应（PCR），有可能鉴定出由于IUGR而导致表观遗传特征和mRNA水平发生改变的肝脏基因。分离鉴定出的其中一个序列包含双特异性磷酸酶-5基因（DUSP5）的外显子2。IUGR影响大鼠成年期肝脏DUSP5 mRNA水平和外显子2的DNA甲基化。DUSP5使丝裂原活化蛋白激酶（MAPK）信号级联反应中的Erk1和Erk2去磷酸化，进而影响胰岛素受体底物-1的丝氨酸612磷酸化（p612 IRS-1）。在成年大鼠肝脏中，IUGR增加了Erk1/Erk2磷酸化和p612 IRS-1磷酸化。肝脏IRS-1丝氨酸磷酸化增加可能导致这些动物出现胰岛素抵抗。我们得出结论，子宫胎盘功能不全诱导的宫内生长迟缓1）影响肝脏DUSP-5的表观遗传特征和mRNA，2）增加成年大鼠肝脏胰岛素受体底物-1丝氨酸612位点的磷酸化。
