LncRNA Osilr9 coordinates promoter DNA demethylation and the intrachromosomal loop structure required for maintaining stem cell pluripotency
LncRNA Osilr9 coordinates promoter DNA demethylation and the intrachromosomal loop structure required for maintaining stem cell pluripotency
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LncRNA Osilr9 协调启动子 DNA 去甲基化和维持干细胞多能性所需的染色体内环结构
DOI：
10.1016/j.ymthe.2022.12.010
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发表时间：
2023-06-07
影响因子：
12.4
通讯作者：
Li，Wei
中科院分区：
文献类型：
--
作者：
Zhu，Yanbo;Yan，Zi;Li，Wei
将体细胞核重编程为多能状态具有创造用于再生医学的患者特异性诱导多能干细胞的潜力。然而，目前，这种多能重编程的表观遗传机制知之甚少。为了描绘这种表观遗传调控网络，我们利用染色质RNA原位逆转录测序（CRIST-seq）方法来鉴定嵌入干细胞核心因子基因的三维染色体内结构中的长非编码RNA（lncRNA）。通过CRIST-seq和RNA测序相结合，我们鉴定了Oct 4-Sox 2相互作用lncRNA 9（Osilr 9）为多能性相关lncRNA，Osilr 9的表达与干细胞重编程中的多能性状态相关。使用短发夹RNA（shRNA）敲低，我们表明这种lncRNA是干细胞多能性的最佳维持所必需的。Osilr 9的过表达可诱导成纤维细胞内源性干细胞核心因子基因的强烈激活，并参与维持多能性所需的染色体内成环。在与Oct 4启动子结合后，Osilr 9募集DNA去甲基化酶10 - 11易位1，导致启动子去甲基化。这些数据表明Osilr 9是一个重要的染色质表观遗传调节因子，协调核心干细胞因子基因的启动子活性，突出了多能性相关lncRNA在干细胞多能性和重编程中的关键作用。
Nuclear reprogramming of somatic cells into a pluripotent status has the potential to create patient-specific induced pluripotent stem cells for regenerative medicine. Currently, however, the epigenetic mechanisms underlying this pluripotent reprogramming are poorly understood. To delineate this epigenetic regulatory network, we utilized a chromatin RNAin situreverse transcription sequencing (CRIST-seq) approach to identify long noncoding RNAs (lncRNAs) embedded in the 3-dimensional intrachromosomal architecture of stem cell core factor genes. By combining CRIST-seq and RNA sequencing, we identifiedOct4-Sox2interacting lncRNA 9 (Osilr9) as a pluripotency-associated lncRNA.Osilr9expression was associated with the status of stem cell pluripotency in reprogramming. Using short hairpin RNA (shRNA) knockdown, we showed that this lncRNA was required for the optimal maintenance of stem cell pluripotency. Overexpression ofOsilr9induced robust activation of endogenous stem cell core factor genes in fibroblasts.Osilr9participated in the formation of the intrachromosomal looping required for the maintenance of pluripotency. After binding to theOct4promoter,Osilr9recruited the DNA demethylase ten-eleven translocation 1, leading to promoter demethylation. These data demonstrate thatOsilr9is a critical chromatin epigenetic modulator that coordinates the promoter activity of core stem cell factor genes, highlighting the critical role of pluripotency-associated lncRNAs in stem cell pluripotency and reprogramming.