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Regulation of DNA methylation and X chromosome inactivation in human embryonic stem cells

机译：人类胚胎干细胞中DNA甲基化和X染色体失活的调控

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摘要

Human embryonic stem cells (hESCs) can self-renew indefinitely while maintaining pluripotency in vitro. However, genetic and epigenetic abnormalities exist after long term culturing of hESCs. Therefore, it is of paramount importance to define and monitor epigenetic changes in hESCs and differentiated progenies. My thesis work examines dynamic changes in DNA methylation and X-inactivation of hESCs and their derivatives.;In this thesis, I first studied the changes of DNA methylation in promoter CpG islands during the conversion and expansion of hESCs into neural precursor cells (NPCs). A wave of de novo methylation in CpG islands takes place during the differentiation. Furthermore, the methylation level in a subset of the promoter CpG islands is higher in hESC-NPCs than primary NPC cells with the reduced expression of associated genes. These genes are involved in cell metabolism, cellular structure, and signal transduction. Collectively, my data show that abnormal CpG island methylation occurs in a subset of genes during the differentiation/expansion of hESC-NPCs; thus the methylation status of cultured hESC derivatives should be monitored and corrected for regenerative medicine.;Secondly, I studied the regulation of XCI in female hESC lines. Three hESC lines cultured in our lab (HSF6, H7, and H9) have completed XCI regardless of the presence or absence of XCI markers. Moreover, the expression of XCI markers is unstable and prone to disappear under sub-optimal culture conditions. Coincident with the loss of XCI markers, DNA methylation in a subset of X-linked CpG islands was decreased with the reactivation of a subset of silenced X-linked alleles. Furthermore, the loss of XCI markers accompanies changes in DNA methylation and expression of autosomal genes.;Thirdly, I compared genome-wide CpG island methylation between hESCs and adult leukocytes, and found a subset of CpG islands differentially methylated between hESCs and leukocytes. The differential methylation at promoter CpG islands is associated with differential gene expression in different cell types, suggesting that DNA methylation contributes to tissue-specific gene expression.;In conclusion, my thesis work demonstrates that epigenetic mechanisms, including DNA methylation and XCI, can significantly affect proper gene expression in both hESCs and their derivatives. Moreover, by monitoring DNA methylation and XCI status we can ensure the safety of the patients who use hESCs for regenerative medicine.
机译：人类胚胎干细胞（hESCs）可以无限自我更新，同时在体外保持多能性。但是，hESCs长期培养后存在遗传和表观遗传异常。因此，至关重要的是定义和监测hESCs和分化后代的表观遗传学变化。我的论文研究了hESCs及其衍生物的DNA甲基化和X失活的动态变化。;本论文，我首先研究了hESCs转化为神经前体细胞（NPC）时启动子CpG岛中DNA甲基化的变化。 。在分化过程中，CpG岛发生了从头甲基化的浪潮。此外，在hESC-NPC中，启动子CpG岛的子集中的甲基化水平高于具有相关基因表达的原代NPC细胞。这些基因参与细胞代谢，细胞结构和信号转导。总的来说，我的数据表明，在hESC-NPCs分化/扩增过程中，异常的CpG岛甲基化发生在一部分基因中。因此，应该对培养的hESC衍生物的甲基化状态进行监测和纠正，以进行再生医学研究。第二，研究雌性hESC细胞系中XCI的调控。无论实验室中是否存在XCI标记，在我们实验室中培养的三个hESC品系（HSF6，H7和H9）均已完成XCI。此外，XCI标记的表达不稳定，在次优培养条件下容易消失。与XCI标记的丢失巧合的是，X连锁的CpG岛子集的DNA甲基化随着沉默的X连锁的等位基因的子集的重新激活而降低。此外，XCI标记的缺失伴随DNA甲基化和常染色体基因表达的变化。第三，我比较了hESC和成年白细胞之间的全基因组CpG岛甲基化，并发现了在hESC和白细胞之间差异甲基化的CpG岛的子集。启动子CpG岛上的甲基化差异与不同细胞类型中基因表达的差异有关，这表明DNA甲基化有助于组织特异性基因的表达。总之，我的论文工作表明表观遗传机制，包括DNA甲基化和XCI，可以显着地促进基因表达。影响hESCs及其衍生物中正确的基因表达。此外，通过监测DNA甲基化和XCI状态，我们可以确保使用hESC进行再生医学的患者的安全性。

著录项

  • 作者

    Shen, Yin.;

  • 作者单位

    University of California, Los Angeles.;

  • 授予单位 University of California, Los Angeles.;
  • 学科 Genetics.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 186 p.
  • 总页数 186
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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