Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons.
Novel epigenetic clock for fetal brain development predicts prenatal age for cellular stem cell models and derived neurons.
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用于胎儿脑发育的新型表观遗传钟可以预测细胞干细胞模型和衍生神经元的产前年龄。
DOI：
10.1186/s13041-021-00810-w
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发表时间：
2021-06-26
期刊：
影响因子：
3.6
通讯作者：
Hannon E
中科院分区：
文献类型：
--
作者：
Steg LC;Shireby GL;Imm J;Davies JP;Franklin A;Flynn R;Namboori SC;Bhinge A;Jeffries AR;Burrage J;Neilson GWA;Walker EM;Perfect LW;Price J;McAlonan G;Srivastava DP;Bray NJ;Cope EL;Jones KM;Allen ND;Pishva E;Dempster EL;Lunnon K;Mill J;Hannon E
诱导多能干细胞（iPSC）及其分化的神经元（iPSC-神经元）是中枢神经系统研究中广泛使用的细胞模型。然而，目前尚不清楚它们如何捕获与年龄相关的过程，特别是考虑到多能细胞仅存在于哺乳动物发育的最早阶段。表观遗传时钟利用DNA甲基化中与年龄相关的协调变化来预测与实际年龄密切相关的变化。已经表明，多能性的诱导使预测的表观遗传年龄年轻化。由于现有的时钟并不适合研究大脑发育，我们开发了胎儿大脑时钟（FBC），这是一种在人类产前大脑样本中训练的定制表观遗传时钟，以便更精确地研究iPSC和iPSC神经元的表观遗传年龄。FBC在两个独立的验证队列中测试，总共194个样本，证实FBC在胎儿大脑队列中优于其他已建立的表观遗传时钟。我们将FBC应用于来自iPSC和胚胎干细胞及其衍生的神经元前体细胞和神经元的DNA甲基化数据，发现这些细胞类型的表观遗传特征为具有早期胎儿年龄。此外，虽然从iPSC向神经元的分化显著增加了表观遗传年龄，但iPSC神经元仍被预测为胎儿。我们的研究结果重申了需要更好地理解现有表观遗传时钟在回答生物学研究问题方面的局限性，并强调了iPSC神经元作为年龄相关疾病细胞模型的局限性。在线版本包含补充材料，可通过10.1186/s13041-021-00810-w获得。
Induced pluripotent stem cells (iPSCs) and their differentiated neurons (iPSC-neurons) are a widely used cellular model in the research of the central nervous system. However, it is unknown how well they capture age-associated processes, particularly given that pluripotent cells are only present during the earliest stages of mammalian development. Epigenetic clocks utilize coordinated age-associated changes in DNA methylation to make predictions that correlate strongly with chronological age. It has been shown that the induction of pluripotency rejuvenates predicted epigenetic age. As existing clocks are not optimized for the study of brain development, we developed the fetal brain clock (FBC), a bespoke epigenetic clock trained in human prenatal brain samples in order to investigate more precisely the epigenetic age of iPSCs and iPSC-neurons. The FBC was tested in two independent validation cohorts across a total of 194 samples, confirming that the FBC outperforms other established epigenetic clocks in fetal brain cohorts. We applied the FBC to DNA methylation data from iPSCs and embryonic stem cells and their derived neuronal precursor cells and neurons, finding that these cell types are epigenetically characterized as having an early fetal age. Furthermore, while differentiation from iPSCs to neurons significantly increases epigenetic age, iPSC-neurons are still predicted as being fetal. Together our findings reiterate the need to better understand the limitations of existing epigenetic clocks for answering biological research questions and highlight a limitation of iPSC-neurons as a cellular model of age-related diseases. The online version contains supplementary material available at 10.1186/s13041-021-00810-w.
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影响因子：
5.7
作者：
Hillary, Robert F.;Stevenson, Anna J.;Marioni, Riccardo E.
通讯作者：
Marioni, Riccardo E.
患者特异性诱导的多能干细胞的效用用于自闭症谱系障碍的建模。
影响因子：
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作者：
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通讯作者：
Price, Jack
在子宫内暴露于孕产妇的吸烟与DNA甲基化的改变有关，并且在发育中的胎儿脑中的神经元含量降低。
影响因子：
3.9
作者：
Chatterton Z;Hartley BJ;Seok MH;Mendelev N;Chen S;Milekic M;Rosoklija G;Stankov A;Trencevsja-Ivanovska I;Brennand K;Ge Y;Dwork AJ;Haghighi F
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作者：
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Levine ME