Expression of a large LINE-1-driven antisense RNA is linked to epigenetic silencing of the metastasis suppressor gene TFPI-2 in cancer.
Expression of a large LINE-1-driven antisense RNA is linked to epigenetic silencing of the metastasis suppressor gene TFPI-2 in cancer.
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DOI：
10.1093/nar/gkt438
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发表时间：
2013-08
影响因子：
14.9
通讯作者：
Tufarelli C
中科院分区：
文献类型：
--
作者：
Cruickshanks HA;Vafadar-Isfahani N;Dunican DS;Lee A;Sproul D;Lund JN;Meehan RR;Tufarelli C
LINE-1逆转录转座子是病毒来源的大量重复元件，其在正常细胞中通过表观遗传机制保持静止。LINE-1的激活经常发生在癌症中，可以使LINE-1动员，但也具有逆转录转座无关的后果。我们以前报道过，在癌症中，异常活性的LINE-1启动子可以驱动侧翼独特序列的转录，产生LINE-1嵌合转录物（LCT）。在这里，我们表明，这样的LCT，LCT 13，是一个大的转录本（>300 kb）运行反义转移抑制基因TFPI-2。我们在转基因小鼠胚胎干（ES）细胞中模拟了TFPI-2的反义RNA表达，并证明反义RNA诱导沉默和抑制性组蛋白修饰的沉积，这意味着因果关系。与此一致，乳腺癌和结肠癌细胞系中的LCT 13表达与TFPI-2的沉默和抑制性染色质相关。此外，我们在56%的结直肠肿瘤中检测到LCT 13转录物，其表现出TFPI-2表达降低。我们的研究结果牵连激活LINE-1元素在随后的表观遗传重塑周围的基因，从而暗示了一个新的逆转录转座独立的作用LINE-1元素在恶性肿瘤。
LINE-1 retrotransposons are abundant repetitive elements of viral origin, which in normal cells are kept quiescent through epigenetic mechanisms. Activation of LINE-1 occurs frequently in cancer and can enable LINE-1 mobilization but also has retrotransposition-independent consequences. We previously reported that in cancer, aberrantly active LINE-1 promoters can drive transcription of flanking unique sequences giving rise to LINE-1 chimeric transcripts (LCTs). Here, we show that one such LCT, LCT13, is a large transcript (>300 kb) running antisense to the metastasis-suppressor gene TFPI-2. We have modelled antisense RNA expression at TFPI-2 in transgenic mouse embryonic stem (ES) cells and demonstrate that antisense RNA induces silencing and deposition of repressive histone modifications implying a causal link. Consistent with this, LCT13 expression in breast and colon cancer cell lines is associated with silencing and repressive chromatin at TFPI-2. Furthermore, we detected LCT13 transcripts in 56% of colorectal tumours exhibiting reduced TFPI-2 expression. Our findings implicate activation of LINE-1 elements in subsequent epigenetic remodelling of surrounding genes, thus hinting a novel retrotransposition-independent role for LINE-1 elements in malignancy.
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影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
7
作者：
Hon, Gary C.;Hawkins, R. David;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
64.5
作者：
Gilbert, N;Lutz-Prigge, S;Moran, JV
通讯作者：
Moran, JV
影响因子：
56.9
作者：
Gaudet, F;Hodgson, JG;Jaenisch, R
通讯作者：
Jaenisch, R
DOI：
10.1016/s0167-4781(00)00298-0
发表时间：
2001-02-16
期刊：
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION
影响因子：
--
作者：
Kamei, S;Kazama, Y;Kisiel, W
通讯作者：
Kisiel, W