Targeted disruption of Hotair leads to homeotic transformation and gene derepression.
Targeted disruption of Hotair leads to homeotic transformation and gene derepression.
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DOI：
10.1016/j.celrep.2013.09.003
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发表时间：
2013-10-17
期刊：
影响因子：
8.8
通讯作者：
Chang HY
中科院分区：
文献类型：
--
作者：
Li L;Liu B;Wapinski OL;Tsai MC;Qu K;Zhang J;Carlson JC;Lin M;Fang F;Gupta RA;Helms JA;Chang HY
长链非编码rna （lncRNA）被认为是基因表达的普遍调控因子，但lncRNA在体内失活的后果大多未知。本研究表明，小鼠Hotair lncRNA的靶向缺失导致数百个基因的去抑制，导致脊柱的同型转化和掌骨-腕骨畸形。RNA-seq和条件失活揭示了Hotair在不影响印迹选择的情况下抑制HoxD基因和一些印迹位点（如Dlk1-Meg3和Igf2-H19）的持续需求。Hotair结合在体内的Polycomb抑制复合体2（在赖氨酸27位点甲基化组蛋白H3）和Lsd1复合体（在赖氨酸4位点去甲基化组蛋白H3）。Hotair失活导致H3K4me3在靶基因上获得，并在较小程度上导致H3K27me3在靶基因上丢失。这些结果揭示了Hotair lncRNA在Hox和其他基因上强制染色质沉默状态的功能和机制。
Long noncoding RNAs (lncRNAs) are thought to be prevalent regulators of gene expression, but the consequences of lncRNA inactivation in vivo are mostly unknown. Here we show that targeted deletion of mouse Hotair lncRNA leads to de-repression of hundreds of genes, resulting in homeotic transformation of the spine and malformation of metacarpal-carpal bones. RNA-seq and conditional inactivation reveal an ongoing requirement of Hotair to repress HoxD genes and several imprinted loci such as Dlk1-Meg3 and Igf2-H19, without affecting imprinting choice. Hotair binds to both Polycomb repressive complex 2 that methylates histone H3 at lysine 27 (H3K27) and Lsd1 complex that demethylates histone H3 at lysine 4 (H3K4) in vivo. Hotair inactivation causes H3K4me3 gain and, to a lesser extent, H3K27me3 loss at target genes. These results reveal the function and mechanisms of Hotair lncRNA to enforce silent chromatin state at Hox and additional genes.
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64.5
作者：
Huarte M;Guttman M;Feldser D;Garber M;Koziol MJ;Kenzelmann-Broz D;Khalil AM;Zuk O;Amit I;Rabani M;Attardi LD;Regev A;Lander ES;Jacks T;Rinn JL
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影响因子：
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