通过全基因组屏幕对L1调节器进行选择性沉默
Nian Liu1, Cameron H Lee2, Tomek Swigut1
1Department of Chemical and Systems Biology, Stanford School of Medicine, Stanford University, Stanford, California 94305, USA.
Nature
|December 7, 2017
概括
像LINE-1 (L1) 这样的可移植元素会影响基因组进化和疾病. 这项研究确定了控制L1活动的基因,揭示了HUSH和MORC2在L1上表观遗传沉默的新途径,改变了宿主基因表达.
科学领域:
- 遗传学
- 表观遗传学
- 分子生物学
背景情况:
- 可转移元素,特别是长间隔元素-1 (LINE-1或L1),是影响基因组进化和引起疾病的移动遗传序列.
- 虽然L1s对于遗传变异至关重要,但它们在宿主基因表达中的精确调节和作用仍然不完全理解.
研究的目的:
- 使用CRISPR-Cas9进行全基因组选,识别调节LINE-1 (L1) 逆转换的基因.
- 阐明包括MORC2和HUSH复合体在内的特定因素限制L1活动的机制.
- 通过表观遗传修饰剂对L1沉默如何影响宿主基因表达.
主要方法:
- 在人类细胞系中进行全基因组CRISPR-Cas9查,以确定L1逆转换的调节者.
- 研究MORC2和HUSH复杂子单元 (MPP8,TASOR) 与L1元素的相互作用.
- 评估L1沉默对基因组修饰 (H3K9me3) 和宿主基因表达的影响.
主要成果:
- 识别各种促进或限制L1逆转换的基因,通常与人类疾病有关.
- 发现HUSH复合体和MORC2可以选择性地结合到全长L1细胞中.
- 证明HUSH和MORC2促进H3K9me3沉积以使L1沉默,降低附近宿主基因的调节.
结论:
- 已经阐明了涉及HUSH和MORC2的新型L1限制途径,突出显示了转子的表观遗传控制.
- 宿主基因中的L1沉默可以重新连接基因表达程序,强调转子和基因组之间的复杂相互作用.
- 这项研究为了解L1逆转换及其对基因组调节和疾病的影响提供了宝贵的资源.
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