Lund Riikka J, Emani Maheswara Reddy, Barbaric Ivana, Kivinen Virpi, Jones Mark, Baker Duncan, Gokhale Paul, Nykter Matti, Lahesmaa Riitta, Andrews Peter W
Centre for Stem Cell Biology, Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN, UK; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku FI-20520, Finland.
Stem Cell Res. 2013 Nov;11(3):1022-36. doi: 10.1016/j.scr.2013.07.002. Epub 2013 Jul 18.
Genomic abnormalities may accumulate in human embryonic stem cells (hESCs) during in vitro maintenance. Characterization of the mechanisms enabling survival and expansion of abnormal hESCs is important due to consequences of genetic changes for the therapeutic utilization of stem cells. Furthermore, these cells provide an excellent model to study transformation in vitro. We report here that the histone deacetylase proteins, HDAC1 and HDAC2, are increased in karyotypically abnormal hESCs when compared to their normal counterparts. Importantly, similar to many cancer cell lines, we found that HDAC inhibitors repress proliferation of the karyotypically abnormal hESCs, whereas normal cells are more resistant to the treatment. The decreased proliferation correlates with downregulation of HDAC1 and HDAC2 proteins, induction of the proliferation inhibitor, cyclin-dependent kinase inhibitor 1A (CDKN1A), and altered regulation of tumor suppressor protein Retinoblastoma 1 (RB1). Through genome-wide transcriptome analysis we have identified genes with altered expression and responsiveness to HDAC inhibition in abnormal cells. Most of these genes are linked to severe developmental and neurological diseases and cancers. Our results highlight the importance of epigenetic mechanisms in the regulation of genomic stability of hESCs, and provide valuable candidates for targeted and selective growth inhibition of karyotypically abnormal cells.
在体外培养过程中，人类胚胎干细胞（hESCs）可能会积累基因组异常。鉴于基因变化对干细胞治疗应用的影响，阐明异常hESCs存活和增殖机制具有重要意义。此外，这些细胞为体外研究细胞转化提供了一个极佳的模型。我们在此报告，与核型正常的hESCs相比，核型异常的hESCs中组蛋白去乙酰化酶蛋白HDAC1和HDAC2的含量有所增加。重要的是，与许多癌细胞系相似，我们发现HDAC抑制剂可抑制核型异常hESCs的增殖，而正常细胞对该处理更具抗性。增殖的降低与HDAC1和HDAC2蛋白的下调、增殖抑制剂细胞周期蛋白依赖性激酶抑制剂1A（CDKN1A）的诱导以及肿瘤抑制蛋白视网膜母细胞瘤1（RB1）调控的改变相关。通过全基因组转录组分析，我们在异常细胞中鉴定出了表达改变且对HDAC抑制有反应的基因。这些基因大多与严重的发育、神经疾病及癌症相关。我们的结果凸显了表观遗传机制在调控hESCs基因组稳定性中的重要性，并为核型异常细胞的靶向和选择性生长抑制提供了有价值的候选靶点。
