金子兵教授团队：首次揭示人类视网膜融合基因图谱并发现调控干细胞分化方向融合RNA

嵌合RNA对人类干细胞分化、干细胞性维持和中枢神经系统发育具有调节作用，已有研究在视网膜发育过程中发现了许多新的嵌合RNA。

北京同仁医院金子兵教授/晋康新教授团队在国际知名学术期刊eLife上发表了题为“RNA fusion in human retinal development”的研究论文，同单位的王文主任为本文第一作者。该研究首次绘制了人类视网膜的融合RNA图谱，并发现CTNNBIP1-CLSTN1融合RNA具有调控人视网膜细胞分化方向的重要功能，CTNNBIP1-CLSTN1敲低使神经视网膜细胞分化效能降低，而有效促进视网膜色素上皮（RPE）分化。

在癌细胞和健康的人类细胞中都发现了嵌合RNA。它是由不同亲本基因的核苷酸序列组成的转录本，可以进一步形成功能受损的野生型蛋白质、全新的融合蛋白质和新的非编码RNA，对细胞分化和个体发育产生调节作用，其在神经系统发育中的作用尤为关键。基于人类胚胎电子干细胞来源的视网膜类器官（ROs），从第0天到第120天，贯穿整个发育中的ROs的嵌合RNA的表达图谱。研究揭示了CTCL普遍存在于人类视网膜、ROs和视网膜细胞系中，其功能的丧失使干细胞同视网膜色素上皮细胞一样的结局，即以牺牲视网膜细胞为代价。

嵌合RNA作为转录组的一部分广泛存在于人类正常组织和肿瘤组织中，可以调节单个细胞的活动。研究发现嵌合RNA在RO发育的所有阶段都有表达。嵌合RNA CTCL在人类视网膜中广泛表达，但在小鼠视网膜中不表达，对于视网膜干细胞（RPCs）分化为神经视网膜（NR）或视网膜色素上皮（RPE）至关重要。CTCL表达水平相对较高的RPCs会分化为NR，而CTCL表达水平相对较低的RPCs会向RPE分化。

图1.嵌合RNA检测的一般方案

注：（上图）从多功能干细胞中生成人类视网膜类器官（ROs）的程序。（中图）D0-120人ROs用于批量RNA测序。（下图）嵌合RNA筛选过程和标准的说明。

该研究首次明确了融合RNA在人视网膜正常发育中广泛且持续表达，绘制了多时间点正常人视网膜发育中嵌合RNA表达图谱，为异常视网膜发育和疾病状态下的视网膜中的嵌合RNA研究明确了基线，揭示了RNA在人视网膜发育及细胞分化中的关键作用，是干细胞视网膜再生领域的重要发现。

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