Meg3 Non-coding RNA Expression Controls Imprinting by Preventing Transcriptional Upregulation in cis
Meg3 Non-coding RNA Expression Controls Imprinting by Preventing Transcriptional Upregulation in cis
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DOI：
10.1016/j.celrep.2018.03.044
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发表时间：
2018-04-10
期刊：
影响因子：
8.8
通讯作者：
Feil, Robert
中科院分区：
文献类型：
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作者：
Sanli, Ildem;Lalevee, Sebastien;Feil, Robert
虽然许多长链非编码RNA（lncRNA）是印记的，但它们的作用往往仍然未知。Dlk 1-Dio 3结构域在母体染色体上表达lncRNA Meg 3和多种microRNA和小核仁RNA（snoRNA），并构成发育的表观遗传模型。该结构域的Dlk 1（Delta-like-1）基因编码抑制Notch 1信号传导并调节多种发育过程的配体。使用混合胚胎干细胞（ESC）系统，我们发现，Dlk 1成为在神经分化过程中的印记，这涉及父染色体上的转录上调。母体Dlk 1基因保持稳定。其针对活化的保护作用由Meg 3表达顺式控制，并且还需要H3-Lys-27甲基转移酶Ezh 2。此外，母体Meg 3表达还可防止其启动子处的从头DNA甲基化。我们发现，Meg 3 lncRNA是部分保留在顺式和重叠的母体Dlk 1在胚胎细胞。结合，我们的数据唤起了一个印迹模型，其中等位基因lncRNA表达阻止基因激活顺式。
Although many long non-coding RNAs (lncRNAs) are imprinted, their roles often remain unknown. The Dlk1-Dio3 domain expresses the lncRNA Meg3 and multiple microRNAs and small nucleolar RNAs (snoRNAs) on the maternal chromosome and constitutes an epigenetic model for development. The domain's Dlk1 (Delta-like-1) gene encodes a ligand that inhibits Notch1 signaling and regulates diverse developmental processes. Using a hybrid embryonic stem cell (ESC) system, we find that Dlk1 becomes imprinted during neural differentiation and that this involves transcriptional upregulation on the paternal chromosome. The maternal Dlk1 gene remains poised. Its protection against activation is controlled in cis by Meg3 expression and also requires the H3-Lys-27 methyltransferase Ezh2. Maternal Meg3 expression additionally protects against de novo DNA methylation at its promoter. We find that Meg3 lncRNA is partially retained in cis and overlaps the maternal Dlk1 in embryonic cells. Combined, our data evoke an imprinting model in which allelic lncRNA expression prevents gene activation in cis.