Center for iPS Cell Research and Application (CiRA), Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Knoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Yoshida-Knoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Knoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Yoshida-Knoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Cell Rep. 2021 Nov 2;37(5):109909. doi: 10.1016/j.celrep.2021.109909.
Human induced pluripotent stem cells (hiPSCs) show variable differentiation potential due to their epigenomic heterogeneity, whose extent/attributes remain unclear, except for well-studied elements/chromosomes such as imprints and the X chromosomes. Here, we show that seven hiPSC lines with variable germline potential exhibit substantial epigenomic heterogeneity, despite their uniform transcriptomes. Nearly a quarter of autosomal regions bear potentially differential chromatin modifications, with promoters/CpG islands for H3K27me3/H2AK119ub1 and evolutionarily young retrotransposons for H3K4me3. We identify 145 large autosomal blocks (≥100 kb) with differential H3K9me3 enrichment, many of which are lamina-associated domains (LADs) in somatic but not in embryonic stem cells. A majority of these epigenomic heterogeneities are independent of genetic variations. We identify an X chromosome state with chromosome-wide H3K9me3 that stably prevents X chromosome erosion. Importantly, the germline potential of female hiPSCs correlates with X chromosome inactivation. We propose that inherent genomic properties, including CpG density, transposons, and LADs, engender epigenomic heterogeneity in hiPSCs.
人类诱导多能干细胞（hiPSC）由于其表观基因组异质性而表现出可变的分化潜力，除了印迹和 X 染色体等研究充分的元件/染色体外，其程度/属性尚不清楚。在这里，我们表明，尽管具有统一的转录组，但七种具有可变种系潜力的 hiPSC 系表现出明显的表观基因组异质性。近四分之一的常染色体区域具有潜在的差异染色质修饰，H3K27me3/H2AK119ub1 的启动子/CpG 岛和 H3K4me3 的进化年轻的逆转录转座子。我们鉴定了 145 个具有差异 H3K9me3 富集的大型常染色体块（≥100 kb），其中许多是体细胞而非胚胎干细胞中的核纤层相关结构域（LAD）。这些表观基因组异质性中的大多数与遗传变异无关。我们鉴定了一种具有染色体范围 H3K9me3 的 X 染色体状态，该状态可稳定防止 X 染色体侵蚀。重要的是，女性 hiPSC 的种系潜力与 X 染色体失活相关。我们提出，包括 CpG 密度、转座子和 LAD 在内的固有基因组特性会导致 hiPSC 中的表观基因组异质性。
