Kowalski Thayne Woycinck, Caldas-Garcia Gabriela Barreto, Gomes Julia do Amaral, Fraga Lucas Rosa, Schuler-Faccini Lavínia, Recamonde-Mendoza Mariana, Paixão-Côrtes Vanessa Rodrigues, Vianna Fernanda Sales Luiz
Post-Graduation Program in Genetics and Molecular Biology, PPGBM, Universidade Federal do Rio Grande do Sul, UFRGS, Porto Alegre, Brazil.
Laboratory of Medical Genetics and Evolution, Genetics Department, Universidade Federal do Rio Grande do Sul, UFRGS, Porto Alegre, Brazil.
Front Genet. 2021 Jun 23;12:680217. doi: 10.3389/fgene.2021.680217. eCollection 2021.
The identification of thalidomide-Cereblon-induced SALL4 degradation has brought new understanding for thalidomide embryopathy (TE) differences across species. Some questions, however, regarding species variability, still remain. The aim of this study was to detect sequence divergences between species, affected or not by TE, and to evaluate the regulated gene co-expression in a murine model. Here, we performed a comparative analysis of proteins experimentally established as affected by thalidomide exposure, evaluating 14 species. The comparative analysis, regarding synteny, neighborhood, and protein conservation, was performed in 42 selected genes. Differential co-expression analysis was performed, using a publicly available assay, GSE61306, which evaluated mouse embryonic stem cells (mESC) exposed to thalidomide. The comparative analyses evidenced 20 genes in the upstream neighborhood of , which are different between the species who develop, or not, the classic TE phenotype. Considering protein sequence alignments, RECQL4, SALL4, CDH5, KDR, and NOS2 proteins had the biggest number of variants reported in unaffected species. In co-expression analysis, was a gene identified as a driver of the co-expression of other genes implicated in genetic, non-teratogenic, limb reduction defects (LRD), such as , , , and ; and were shown to have a moderate co-expression correlation, which is affected after thalidomide exposure. Hence, even though the classic TE phenotype is not identified in mice, a deregulatory Crbn-induced mechanism is suggested in this animal. Functional studies are necessary, especially evaluating the genes responsible for LRD syndromes and their interaction with thalidomide-Cereblon.
沙利度胺- Cereblon诱导的SALL4降解的鉴定为跨物种的沙利度胺胚胎病（TE）差异带来了新的认识。然而，关于物种变异性的一些问题仍然存在。本研究的目的是检测受TE影响或未受影响的物种之间的序列差异，并评估小鼠模型中受调控的基因共表达。在这里，我们对实验确定受沙利度胺暴露影响的蛋白质进行了比较分析，评估了14个物种。对42个选定基因进行了关于同线性、邻域和蛋白质保守性的比较分析。使用公开可用的检测方法GSE61306进行差异共表达分析，该方法评估了暴露于沙利度胺的小鼠胚胎干细胞（mESC）。比较分析证明了在 的上游邻域中有20个基因，这些基因在出现或未出现经典TE表型的物种之间是不同的。考虑蛋白质序列比对，RECQL4、SALL4、CDH5、KDR和NOS2蛋白在未受影响的物种中报告的变体数量最多。在共表达分析中， 是一个被确定为与遗传、非致畸性肢体减少缺陷（LRD）相关的其他基因共表达驱动因子的基因，如 、 、 和 ； 和 显示出中等的共表达相关性，在沙利度胺暴露后受到影响。因此，尽管在小鼠中未鉴定出经典的TE表型，但在这种动物中提示了一种去调控的Crbn诱导机制。功能研究是必要的，特别是评估负责LRD综合征的基因及其与沙利度胺- Cereblon的相互作用。
