皮肤表皮是由许多不同细胞类型构成的混合体,每种细胞类型都有非常明确的职责。这样复杂的组织,其生成或分化在细胞水平上需要进行大量的协调,这一过程发生故障可以导致灾难性的后果。来自斯坦福大学医学院的研究人员确定了这一分化过程的一个主要调控因子。

-2013年1月10日版《自然》

中文翻译


【译文】长非编码RNA TINCR控制体细胞组织分化

【译文】成千上万人长非编码RNA(lncRNAs)的功能特点已经被确定了;然而,lncRNAs在体细胞组织分化中的潜在功能尚不清楚。 本研究表明一个长3,700nt的lncRNA——末端分化诱导的ncRNA (TINCR),通过转录后修饰机制控制人表皮分化。TINCR对于关键分化基因的高mRNA丰度是必需的,这些关键基因中有很多在人类皮肤疾病中发生突变,包括FLG、LOR、 ALOXE3、ALOX12B、ABCA12、CASP14和ELOVL3。TINCR缺陷的表皮缺乏末端分化超微结构,包括角质透明蛋白粒和完整片层体。基因组范围的RNA相互作用分析揭示了TINCR与一系列分化的mRNA相互作用。TINCR–mRNA相互作用通过一个25核苷酸的‘TINCR盒’基序而发生的,这种基序在相互作用的mRNA中非常丰富,并且是TINCR结合所必需的。高通量筛选分析TINCR结合约9400个人重组蛋白的能力揭示了TINCR RNA直接结合staufen1 (STAU1)蛋白。STAU1缺陷的组织体现了受损的分化,这与TINCR缺乏是一致的。然而,UPF1和UPF2的丢失并不会产生分化影响,UPF1 和UPF2对于STAU1介导的RNA衰减是必需的。相反,TINCR–STAU1复合物似乎调控分化mRNA的稳定性,例如KRT80。这些数据证实TINCR是体细胞组织分化所必需的关键lncRNA,这种分化通过lncRNA与分化mRNA结合发生以确保它们的表达。

英文原稿


[Title]: Control of somatic tissue differentiation by the long non-coding RNA TINCR

[Authors]:Markus Kretz,1 Zurab Siprashvili,1, 6 Ci Chu,1, 6 Dan E. Webster,1, 6 Ashley Zehnder,1 Kun Qu,1 Carolyn S. Lee,1 Ross J. Flockhart,1 Abigail F. Groff,1 Jennifer Chow,1 Danielle Johnston,1 Grace E. Kim,1 Robert C. Spitale,1 Ryan A. Flynn,1 Grace X. Y. Zheng,1 Subhadra Aiyer,2 Arjun Raj,2 John L. Rinn,3 Howard Y. Chang1, 4 & Paul A. Khavari1, 5

[Abstract]Several of the thousands of human long non-coding RNAs (lncRNAs) have been functionally characterized; however, potential roles for lncRNAs in somatic tissue differentiation remain poorly understood. Here we show that a 3.7-kilobase lncRNA, terminal differentiation-induced ncRNA (TINCR), controls human epidermal differentiation by a post-transcriptional mechanism. TINCR is required for high messenger RNA abundance of key differentiation genes, many of which are mutated in human skin diseases, including FLG, LOR, ALOXE3, ALOX12B, ABCA12, CASP14 and ELOVL3. TINCR-deficient epidermis lacked terminal differentiation ultrastructure, including keratohyalin granules and intact lamellar bodies. Genome-scale RNA interactome analysis revealed that TINCR interacts with a range of differentiation mRNAs. TINCR–mRNA interaction occurs through a 25-nucleotide ‘TINCR box’ motif that is strongly enriched in interacting mRNAs and required for TINCR binding. A high-throughput screen to analyse TINCR binding capacity to approximately 9,400 human recombinant proteins revealed direct binding of TINCR RNA to the staufen1 (STAU1) protein. STAU1-deficient tissue recapitulated the impaired differentiation seen with TINCR depletion. Loss of UPF1 and UPF2, both of which are required for STAU1-mediated RNA decay, however, did not have differentiation effects. Instead, the TINCR–STAU1 complex seems to mediate stabilization of differentiation mRNAs, such as KRT80. These data identify TINCR as a key lncRNA required for somatic tissue differentiation, which occurs through lncRNA binding to differentiation mRNAs to ensure their expression.

原文地址

http://www.nature.com/nature/journal/v493/n7431/full/nature11661.html

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