Lsh regulates LTR retrotransposon repression independently of Dnmt3b function.
Lsh regulates LTR retrotransposon repression independently of Dnmt3b function.
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DOI：
10.1186/gb-2013-14-12-r146
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发表时间：
2013-12-24
期刊：
影响因子：
12.3
通讯作者：
Meehan RR
中科院分区：
文献类型：
--
作者：
Dunican DS;Cruickshanks HA;Suzuki M;Semple CA;Davey T;Arceci RJ;Greally J;Adams IR;Meehan RR
DNA甲基化通过抑制重复相关的转座来促进基因组的完整性。除了典型的DNA甲基转移酶外，还需要几种辅助染色质因子来维持基因间和卫星重复的DNA甲基化。Lsh是一种染色质解旋酶，它与从头开始的甲基转移酶Dnmt3b之间的相互作用促进了干细胞基因甲基化的沉积，而干细胞基因在Lsh−/−胚胎中是低甲基化的。我们希望确定是否有类似的靶向机制来维持重复序列上的DNA甲基化。我们在LSH−/−和Dnmt3b−/−体细胞中定位了全基因组DNA甲基化模式。脱氧核糖核酸甲基化主要在−/−细胞中特定的基因组重复序列中丢失：反转录转座子、LINE-1重复序列和小鼠卫星。Rna-seq实验表明，在LSH−/−细胞中，特定的IAP LTRs和卫星转录因子，而不是LINE-1元件，被异常转录。在DNMT3b−/−细胞中，ltr的甲基化程度较低，而iap、line-1和卫星元件的甲基化程度较低，但没有表达。LSH−/−细胞中被抑制的LINE-1元件获得H3K4me3，但H3K9me3水平没有改变，表明仅DNA低甲基化对它们的转录激活是不允许的。错误表达的IAP和卫星在LSH−/−细胞中丢失H3K9me3，获得H3K4me3。我们的研究强调，LSH和DNA甲基化对重复元件的调节是选择性的和上下文相关的。体细胞中重复序列的沉默似乎并不是严重依赖于Dnmt3b的功能。我们提出了一个模型，其中LSH在精确的发育窗口被明确要求，以从头开始甲基化为重复序列，随后由Dnmt1维持，以强制选择性重复沉默。
DNA methylation contributes to genomic integrity by suppressing repeat-associated transposition. In addition to the canonical DNA methyltransferases, several auxiliary chromatin factors are required to maintain DNA methylation at intergenic and satellite repeats. The interaction between Lsh, a chromatin helicase, and the de novo methyltransferase Dnmt3b facilitates deposition of DNA methylation at stem cell genes, which are hypomethylated in Lsh−/− embryos. We wished to determine if a similar targeting mechanism operates to maintain DNA methylation at repetitive sequences. We mapped genome-wide DNA methylation patterns in Lsh−/− and Dnmt3b−/− somatic cells. DNA methylation is predominantly lost from specific genomic repeats in Lsh−/− cells: LTR -retrotransposons, LINE-1 repeats and mouse satellites. RNA-seq experiments demonstrate that specific IAP LTRs and satellites, but not LINE-1 elements, are aberrantly transcribed in Lsh−/− cells. LTR hypomethylation in Dnmt3b−/− cells is moderate, whereas IAP, LINE-1 and satellite elements are hypomethylated but silent. Repressed LINE-1 elements in Lsh−/− cells gain H3K4me3, but H3K9me3 levels are unaltered, indicating that DNA hypomethylation alone is not permissive for their transcriptional activation. Mis-expressed IAPs and satellites lose H3K9me3 and gain H3K4me3 in Lsh−/− cells. Our study emphasizes that regulation of repetitive elements by Lsh and DNA methylation is selective and context dependent. Silencing of repeats in somatic cells appears not to be critically dependent on Dnmt3b function. We propose a model where Lsh is specifically required at a precise developmental window to target de novo methylation to repeat sequences, which is subsequently maintained by Dnmt1 to enforce selective repeat silencing.
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影响因子：
4
作者：
Burrage, Joe;Termanis, Ausma;Stancheva, Irina
通讯作者：
Stancheva, Irina
影响因子：
16
作者：
Freitag, M;Hickey, PC;Selker, EU
通讯作者：
Selker, EU
DOI：
10.1111/j.1742-4658.2011.08281.x
发表时间：
2011-10
期刊：
The FEBS journal
影响因子：
--
作者：
Flaus A;Owen-Hughes T
通讯作者：
Owen-Hughes T
影响因子：
3.5
作者：
Kato, Yuzuru;Kaneda, Masahiro;Sasaki, Hiroyuki
通讯作者：
Sasaki, Hiroyuki
影响因子：
3.5
作者：
Jarvis, CD;Geiman, T;Muegge, K
通讯作者：
Muegge, K