Department of Genetics, Stanford University School of Medicine, Stanford, California, 94305, USA.
Genetics Bioinformatics Service Center, Stanford University School of Medicine, Stanford, California, 94304, USA.
Sci Rep. 2018 Aug 28;8(1):12960. doi: 10.1038/s41598-018-31192-0.
13-cis-retinoic acid (isotretinoin, INN) is an oral pharmaceutical drug used for the treatment of skin acne, and is also a known teratogen. In this study, the molecular mechanisms underlying INN-induced developmental toxicity during early cardiac differentiation were investigated using both human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs). Pre-exposure of hiPSCs and hESCs to a sublethal concentration of INN did not influence cell proliferation and pluripotency. However, mesodermal differentiation was disrupted when INN was included in the medium during differentiation. Transcriptomic profiling by RNA-seq revealed that INN exposure leads to aberrant expression of genes involved in several signaling pathways that control early mesoderm differentiation, such as TGF-beta signaling. In addition, genome-wide chromatin accessibility profiling by ATAC-seq suggested that INN-exposure leads to enhanced DNA-binding of specific transcription factors (TFs), including HNF1B, SOX10 and NFIC, often in close spatial proximity to genes that are dysregulated in response to INN treatment. Altogether, these results identify potential molecular mechanisms underlying INN-induced perturbation during mesodermal differentiation in the context of cardiac development. This study further highlights the utility of human stem cells as an alternative system for investigating congenital diseases of newborns that arise as a result of maternal drug exposure during pregnancy.
13-顺式视黄酸（异维 A 酸，INN）是一种用于治疗皮肤痤疮的口服药物，也是一种已知的致畸剂。在这项研究中，使用人诱导多能干细胞（hiPSC）和人胚胎干细胞（hESC）研究了 INN 在心脏早期分化过程中诱导发育毒性的分子机制。在 hiPSC 和 hESC 中预先暴露于亚致死浓度的 INN 不会影响细胞增殖和多能性。然而，当 INN 在分化过程中包含在培养基中时，中胚层分化被破坏。通过 RNA-seq 进行的转录组分析显示，INN 暴露导致参与控制早期中胚层分化的几个信号通路的基因表达异常，例如 TGF-β信号通路。此外，通过 ATAC-seq 进行的全基因组染色质可及性分析表明，INN 暴露导致特定转录因子（TF）的 DNA 结合增强，包括 HNF1B、SOX10 和 NFIC，通常与 INN 处理后失调的基因密切空间接近。总的来说，这些结果确定了 INN 在心脏发育过程中诱导中胚层分化过程中失调的潜在分子机制。这项研究进一步强调了人类干细胞作为研究因母亲在怀孕期间药物暴露而导致新生儿先天性疾病的替代系统的效用。
