Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Peking University Teaching Hospital, Beijing 100020, P.R. China.
Mol Med Rep. 2018 Jun;17(6):8031-8038. doi: 10.3892/mmr.2018.8900. Epub 2018 Apr 19.
The association between apoptosis and neural tube defects (NTDs) is recognized as important, however, the precise link remains to be elucidated. Epigenetic modifications in human NTDs have been detected previously. In the present study, the occurrence of epigenetic modifications in apoptosis‑related genes was investigated in a retinoic acid (RA)‑induced mouse NTD model. Among 84 key genes involved in programmed cell death, 13 genes, including tumor necrosis factor (Tnf), annexin A5, apoptosis inhibitor 5, Bcl2‑associated athanogene 3, baculoviral IAP repeat‑containing 3, caspase (Casp)12, Casp4, Casp8, lymphotoxin β receptor, NLR family, apoptosis inhibitory protein 2, TNF receptor superfamily (Tnfrsf)1a, TNF superfamily (Tnfs)f10 and Tnfsf12, were downregulated, whereas nucleolar protein 3 was upregulated in the RA‑induced NTD mice. Chromatin immunoprecipitation assays revealed that the regulatory regions of these differentially expressed TNF‑related genes showed reduced histone H3K27 acetylation in NTDs, compared with control mice without NTDs. Reverse transcription‑quantitative polymerase chain reaction revealed that H3K27ac‑binding to the differentially regulated genes was markedly decreased in the NTD mice, whereas binding to the unchanged genes Casp3 and Nfkb1 was unaffected. In conclusion, certain TNF‑related genes appeared to be downregulated in NTDs, possibly as a result of abnormal histone H3K27 acetylation. These results shed new light on the epigenetic dysregulation of apoptosis‑related genes in NTDs.
细胞凋亡与神经管缺陷 (NTDs) 之间的关联已得到公认，但确切的联系仍有待阐明。先前已经检测到人类 NTD 中的表观遗传修饰。在本研究中，研究了维甲酸 (RA) 诱导的小鼠 NTD 模型中与细胞凋亡相关的基因中表观遗传修饰的发生情况。在涉及程序性细胞死亡的 84 个关键基因中，包括肿瘤坏死因子 (TNF)、膜联蛋白 A5、凋亡抑制因子 5、Bcl2 相关抗凋亡基因 3、杆状病毒 IAP 重复序列 3、半胱天冬酶 (Caspase)12、Caspase4、Caspase8、淋巴毒素 β 受体、NLR 家族、凋亡抑制蛋白 2、TNF 受体超家族 (Tnfrsf)1a、TNF 超家族 (Tnfs)f10 和 Tnfsf12 的 13 个基因下调，而核仁蛋白 3 在 RA 诱导的 NTD 小鼠中上调。染色质免疫沉淀分析显示，与无 NTD 的对照小鼠相比，这些差异表达的 TNF 相关基因的调控区域在 NTD 中表现出组蛋白 H3K27 乙酰化减少。逆转录-定量聚合酶链反应显示，NTD 小鼠中差异调节基因的 H3K27ac 结合明显减少，而不变基因 Casp3 和 Nfkb1 的结合不受影响。总之，某些 TNF 相关基因在 NTD 中似乎下调，可能是由于组蛋白 H3K27 乙酰化异常所致。这些结果为 NTD 中与细胞凋亡相关的基因的表观遗传失调提供了新的见解。
