Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators.
Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators.
复制标题
全基因组筛选对L1调节剂的选择性沉默对圣体的L1s的选择性沉默。
DOI：
10.1038/nature25179
复制
发表时间：
2018-01-11
期刊：
影响因子：
64.8
通讯作者：
Wysocka J
中科院分区：
文献类型：
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作者：
Liu N;Lee CH;Swigut T;Grow E;Gu B;Bassik MC;Wysocka J
转座因子（Transposable elements，TEs）不仅被认为是寄生DNA，其在基因组中的传播必须由宿主控制，而且在基因组进化和调控中也是主要的参与者。长插入元件-1（LINE-1或L1）是目前人类中唯一的自主移动的转座子，占基因组的17%，并继续产生个体间和个体内的遗传变异，在某些情况下导致疾病。尽管如此，L1活性是如何控制的，L1在宿主基因调控中起着什么样的作用仍然没有完全了解。在这里，我们在两种不同的人类细胞系中使用CRISPR/Cas9筛选策略，以提供参与L1逆转录转座控制的基因的第一个全基因组调查。我们确定了功能多样的基因，无论是促进或限制L1逆转录转座。这些基因通常与人类疾病相关，在转录或转录后水平控制L1生命周期，并且以依赖于内源性L1序列的方式控制L1生命周期，这强调了L1调控的复杂性。我们进一步研究了MORC 2和人类沉默枢纽（HUSH）复合物亚基MPP 8和TASOR对L1的限制。HUSH/MORC 2选择性结合位于转录允许常染色质环境中的进化上年轻的全长L1，并促进H3 K9 me 3沉积以实现转录沉默。有趣的是，这些沉默事件通常发生在转录活性基因的内含子内，并以HUSH/MORC 2依赖性方式导致宿主基因表达下调。总之，我们提供了一个丰富的资源，L1反转录转座的研究，阐明了一种新的L1限制途径，并说明如何表观遗传沉默的TEs重新布线宿主基因表达程序。
Transposable elements (TEs) are now recognized not only as parasitic DNA, whose spread in the genome must be controlled by the host, but also as major players in genome evolution and regulation. Long INterspersed Element-1 (LINE-1 or L1), the only currently autonomous mobile transposon in humans, occupies 17% of the genome and continues to generate inter- and intra-individual genetic variation, in some cases resulting in disease. Nonetheless, how L1 activity is controlled and what function L1s play in host gene regulation remain incompletely understood. Here, we use CRISPR/Cas9 screening strategies in two distinct human cell lines to provide the first genome-wide survey of genes involved in L1 retrotransposition control. We identified functionally diverse genes that either promote or restrict L1 retrotransposition. These genes, often associated with human diseases, control the L1 lifecycle at transcriptional or post-transcriptional levels and in a manner that can depend on the endogenous L1 sequence, underscoring the complexity of L1 regulation. We further investigated L1 restriction by MORC2 and human silencing hub (HUSH) complex subunits MPP8 and TASOR. HUSH/MORC2 selectively bind evolutionarily young, full-length L1s located within transcriptionally permissive euchromatic environment, and promote H3K9me3 deposition for transcriptional silencing. Interestingly, these silencing events often occur within introns of transcriptionally active genes and lead to down-regulation of host gene expression in a HUSH/MORC2-dependent manner. Together, we provide a rich resource for studies of L1 retrotransposition, elucidate a novel L1 restriction pathway, and illustrate how epigenetic silencing of TEs rewires host gene expression programs.
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DOI：
10.1146/annurev-genom-082509-141802
发表时间：
2011
影响因子：
8.7
作者：
Beck CR;Garcia-Perez JL;Badge RM;Moran JV
通讯作者：
Moran JV
影响因子：
9.8
作者：
Brouha, B;Meischl, C;Kazazian, HH
通讯作者：
Kazazian, HH
影响因子：
64.8
作者：
Han, JS;Boeke, JD
通讯作者：
Boeke, JD
影响因子：
46.9
作者：
Morgens DW;Deans RM;Li A;Bassik MC
通讯作者：
Bassik MC
影响因子：
64.8
作者：
通讯作者：
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