Laboratory of Developmental Chronobiology, Institute of Anatomy, Histology and Pathology, Faculty of Medicine, Universidad Austral de Chile, Valdivia, Chile.
J Mol Cell Cardiol. 2014 Jan;66:1-11. doi: 10.1016/j.yjmcc.2013.10.020. Epub 2013 Nov 4.
We recently reported that gestational chronodisruption induces fetal growth restriction and marked effects on fetal adrenal physiology. Here, whole-transcriptome profiling was used to test whether gestational chronodisruption modifies gene expression in the fetal heart, potentially altering cardiac development. At day 10 of gestation (E10), pregnant rats were randomized in two groups: constant light (LL) and control 12 h light/12 h dark photoperiod (LD). RNA isolated from E18 heart was subjected to microarray analysis (Affymetrix platform for 28,000 genes). Integrated transcriptional changes were assessed by gene ontology and pathway analysis. Significant differential expression was found for 383 transcripts in LL relative to LD fetal heart (280 up-regulated and 103 down-regulated); with 42 of them displaying a 1.5-fold or greater change in gene expression. Deregulated markers of cardiovascular disease accounted for alteration of diverse gene networks in LL fetal heart, including local steroidogenesis and vascular calcification, as well as cardiac hypertrophy, stenosis and necrosis/cell death. DNA integrity was also overrepresented, including a 2.1-fold increase of Hmga1 mRNA, which encodes for a profuse architectural transcription factor. microRNA analysis revealed up-regulation of miRNAs 218-1 and 501 and concurrent down-regulation of their validated target genes. In addition, persistent down-regulation of Kcnip2 mRNA and hypertrophy of the left ventricle were found in the heart from 90 days-old offspring from LL mothers. The dysregulation of a relevant fraction of the fetal cardiac transcriptome, together with the diversity and complexity of the gene networks altered by gestational chronodisruption, suggest enduring molecular changes which may shape the hypertrophy observed in the left ventricle of adult LL offspring.
我们最近报道了妊娠期时间扰乱会导致胎儿生长受限，并对胎儿肾上腺生理学产生显著影响。在这里，我们使用全转录组谱分析来测试妊娠期时间扰乱是否会改变胎儿心脏的基因表达，从而潜在地改变心脏发育。在妊娠第 10 天（E10），将怀孕的大鼠随机分为两组：持续光照（LL）和对照 12 小时光照/12 小时黑暗光周期（LD）。从 E18 心脏分离的 RNA 进行微阵列分析（Affymetrix 平台用于 28000 个基因）。通过基因本体论和途径分析评估整合转录变化。在 LL 相对于 LD 胎儿心脏中，发现有 383 个转录本存在显著差异表达（280 个上调和 103 个下调）；其中 42 个转录本的基因表达变化倍数为 1.5 倍或更高。心血管疾病的失调标志物表明，LL 胎儿心脏中的多种基因网络发生了改变，包括局部类固醇生成和血管钙化，以及心脏肥大、狭窄和坏死/细胞死亡。DNA 完整性也被过度表示，包括 Hmga1 mRNA 的 2.1 倍增加，该基因编码一种丰富的结构转录因子。microRNA 分析显示 miR-218-1 和 miR-501 的上调以及它们的验证靶基因的下调。此外，在 LL 母亲的 90 天大的后代的心脏中，还发现了 Kcnip2 mRNA 的持续下调和左心室肥大。胎儿心脏转录组的一个相关部分的失调，以及妊娠期时间扰乱改变的基因网络的多样性和复杂性，表明可能存在持久的分子变化，这些变化可能会影响成年 LL 后代左心室的肥大。
