Wallenberg Neuroscience Center and Lund Stem Cell Center, Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, BMC A11, Lund University, 221 84, Lund, Sweden.
Center for Hematology and Regenerative Medicine Huddinge, Karolinska Institute, 141 52, Stockholm, Sweden.
Nat Commun. 2019 Jul 18;10(1):3182. doi: 10.1038/s41467-019-11150-8.
DNA methylation contributes to the maintenance of genomic integrity in somatic cells, in part through the silencing of transposable elements. In this study, we use CRISPR-Cas9 technology to delete DNMT1, the DNA methyltransferase key for DNA methylation maintenance, in human neural progenitor cells (hNPCs). We observe that inactivation of DNMT1 in hNPCs results in viable, proliferating cells despite a global loss of DNA CpG-methylation. DNA demethylation leads to specific transcriptional activation and chromatin remodeling of evolutionarily young, hominoid-specific LINE-1 elements (L1s), while older L1s and other classes of transposable elements remain silent. The activated L1s act as alternative promoters for many protein-coding genes involved in neuronal functions, revealing a hominoid-specific L1-based transcriptional network controlled by DNA methylation that influences neuronal protein-coding genes. Our results provide mechanistic insight into the role of DNA methylation in silencing transposable elements in somatic human cells, as well as further implicating L1s in human brain development and disease.
DNA 甲基化有助于维持体细胞的基因组完整性，部分是通过沉默转座元件实现的。在这项研究中，我们使用 CRISPR-Cas9 技术在人神经祖细胞 (hNPCs) 中删除 DNA 甲基转移酶 1 (DNMT1)，这是维持 DNA 甲基化的关键酶。我们观察到，尽管 hNPCs 中的 DNA CpG 甲基化整体丢失，但 DNMT1 的失活导致了存活和增殖的细胞。DNA 去甲基化导致进化上年轻的、人科特异性的 LINE-1 元件 (L1s) 的特异性转录激活和染色质重塑，而较老的 L1s 和其他类别的转座元件仍然沉默。激活的 L1s 作为许多参与神经元功能的蛋白编码基因的替代启动子，揭示了受 DNA 甲基化控制的人科特异性基于 L1 的转录网络，该网络影响神经元蛋白编码基因。我们的研究结果为 DNA 甲基化在沉默体细胞中转座元件的作用提供了机制上的见解，并进一步表明 L1s 在人类大脑发育和疾病中发挥作用。
