Fetal growth restriction alters transcription factor binding and epigenetic mechanisms of renal 11β-hydroxysteroid dehydrogenase type 2 in a sex-specific manner
Fetal growth restriction alters transcription factor binding and epigenetic mechanisms of renal 11β-hydroxysteroid dehydrogenase type 2 in a sex-specific manner
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DOI：
10.1152/ajpregu.00122.2010
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发表时间：
2010-07-01
影响因子：
2.8
通讯作者：
Lane, Robert H.
中科院分区：
文献类型：
--
作者：
Baserga, Mariana;Kaur, Rajwinderjit;Lane, Robert H.
Baserga M，Kaur R，黑尔MA，Bares A，Yu X，Callaway CW，McKnight RA，Lane RH.胎儿生长受限以性别特异性方式改变肾11 β-羟基类固醇脱氢酶2型的转录因子结合和表观遗传机制Am J Physiol Regul Integr Comp Physiol 299：R334-R342，2010年。首次发表于2010年4月28日; doi：10.1152/ajpregu.00122.2010.-宫内生长受限（IUGR）增加了严重的成人疾病，如高血压的风险。在IUGR大鼠高血压模型中，我们报道了从出生到出生后（P）第21天肾脏11 β-羟基类固醇脱氢酶2型（11 β-HSD 2）mRNA和蛋白水平的持续下降。这种酶缺乏可通过限制肾糖皮质激素失活而导致高血压。在本研究中，我们假设IUGR影响肾脏染色质结构的11 β-HSD 2表观遗传决定因素，并改变与11 β-HSD 2启动子结合的关键转录因子，并持续下调其mRNA表达。为了验证这一假设，我们对妊娠第19.5天的胚胎大鼠进行双侧子宫动脉结扎，并在第0天（P0）和P21收获肾脏。可影响11 β-HSD 2表达的关键转录因子包括转录增强子特异性蛋白1（SP1）和NF-κ B p65以及转录抑制子早期生长反应因子（Egr-1）和NF-κ B p50。结果表明：（1）IUGR组男性SP 1和NF-κ B B（p65）与11 β-HSD 2启动子的结合显著降低，而女性Egr-1和NF-κ B B（p50）与11 β-HSD 2启动子的结合显著升高; 2）IUGR增加了CpG甲基化状态，P0时11 β-HSD 2启动子多个CpG位点的甲基化改变也具有性别特异性;（3）IUGR组11 β-HSD 2第5外显子H3 K36三甲基化水平在P0和P21时均降低。我们的结论是，IUGR与改变转录抑制/激活剂结合与增加甲基化在11 β-HSD 2启动子区域的性别特异性的方式，可能导致转录活性降低。此外，IUGR降低了两种性别的11 β-HSD 2基因的H3 K36的三甲基化，这与转录延长减少有关。我们推测转录因子结合和染色质结构的改变在子宫内重编程中起作用。
Baserga M, Kaur R, Hale MA, Bares A, Yu X, Callaway CW, McKnight RA, Lane RH. Fetal growth restriction alters transcription factor binding and epigenetic mechanisms of renal 11 beta-hydroxysteroid dehydrogenase type 2 in a sex-specific manner. Am J Physiol Regul Integr Comp Physiol 299: R334-R342, 2010. First published April 28, 2010; doi: 10.1152/ajpregu.00122.2010.-Intrauterine growth restriction (IUGR) increases the risk of serious adult morbidities such as hypertension. In an IUGR rat model of hypertension, we reported a persistent decrease in kidney 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) mRNA and protein levels from birth through postnatal (P) day 21. This enzyme deficiency can lead to hypertension by limiting renal glucocorticoid deactivation. In the present study, we hypothesized that IUGR affects renal 11 beta-HSD2 epigenetic determinants of chromatin structure and alters key transcription factor binding to the 11 beta-HSD2 promoter in association with persistent downregulation of its mRNA expression. To test this hypothesis, we performed bilateral uterine artery ligation on embryonic day 19.5 pregnant rats and harvested kidneys at day 0 (P0) and P21. Key transcription factors that can affect 11 beta-HSD2 expression include transcriptional enhancers specificity protein 1 (SP1) and NF-kappa B p65 and transcriptional repressors early growth response factor (Egr-1) and NF-kappa B p50. Our most important findings were as follows: 1) IUGR significantly decreased SP1 and NF-kappa B (p65) binding to the 11 beta-HSD2 promoter in males, while it increased Egr-1 binding in females and NF-kappa B (p50) binding in males; 2) IUGR increased CpG methylation status, as well as modified the pattern of methylation in several CpG sites of 11 beta-HSD2 promoter at P0 also in a sex-specific manner; and 3) IUGR decreased trimethylation of H3K36 in exon 5 of 11 beta-HSD2 at P0 and P21 in both genders. We conclude that IUGR is associated with altered transcriptional repressor/activator binding in connection with increased methylation in the 11 beta-HSD2 promoter region in a sex-specific manner, possibly leading to decreased transcriptional activity. Furthermore, IUGR decreased trimethylation of H3K36 of the 11 beta-HSD2 gene in both genders, which is associated with decreased transcriptional elongation. We speculate that alterations in transcription factor binding and chromatin structure play a role in in utero reprogramming.