RBFOX splicing factors contribute to a broad but selective recapitulation of peripheral tissue splicing patterns in the thymus.
RBFOX splicing factors contribute to a broad but selective recapitulation of peripheral tissue splicing patterns in the thymus.
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DOI：
10.1101/gr.275245.121
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发表时间：
2021-11
期刊：
影响因子：
7
通讯作者：
Sansom SN
中科院分区：
文献类型：
--
作者：
Jansen K;Shikama-Dorn N;Attar M;Maio S;Lopopolo M;Buck D;Holländer GA;Sansom SN
胸腺上皮细胞（TEC）控制对病原体反应但对自身耐受的T细胞库的选择。已知该过程涉及几乎整个蛋白质编码基因库的混杂表达，但是TEC重演外周同种型的程度以及它们这样做的机制在很大程度上仍然未知。我们进行了第一次组装为基础的转录本结构和剪接因子（SF）的表达在小鼠髓质TEC（mTEC）和21外周组织的转录本普查。成熟的mTEC表达60.1%的所有蛋白质编码的转录本，超过检测到的任何外周组织。然而，对于具有组织限制性表达的基因，mTEC产生的同种型比相关的外周组织少。外显子包含的分析显示，在mTEC的脑特异性微外显子的情况下。我们在TEC中没有发现异常数量的新转录本，并且我们表明，Aire，混杂基因表达的促进者，促进长“经典”转录本（具有5′和3′ UTR）的产生，但对mTEC中的选择性剪接只有有限的影响。SF在mTEC中表达的综合评估确定了一小组非混杂表达的SF基因，其中我们证实RBFOX与AIRE一起存在于mTEC细胞核中。使用条件性功能丧失方法，我们表明Rbfox 2促进mTEC发育并调节混杂表达基因的选择性剪接。这些数据表明，TEC重新启动少量的外周SF，包括RBFOX家族的成员，以产生广泛的，但选择性的外周剪接异构体库的代表。
Thymic epithelial cells (TEC) control the selection of a T cell repertoire reactive to pathogens but tolerant of self. This process is known to involve the promiscuous expression of virtually the entire protein-coding gene repertoire, but the extent to which TEC recapitulate peripheral isoforms, and the mechanisms by which they do so, remain largely unknown. We performed the first assembly-based transcriptomic census of transcript structures and splicing factor (SF) expression in mouse medullary TEC (mTEC) and 21 peripheral tissues. Mature mTEC expressed 60.1% of all protein-coding transcripts, more than was detected in any of the peripheral tissues. However, for genes with tissue-restricted expression, mTEC produced fewer isoforms than did the relevant peripheral tissues. Analysis of exon inclusion revealed an absence of brain-specific microexons in mTEC. We did not find unusual numbers of novel transcripts in TEC, and we show that Aire, the facilitator of promiscuous gene expression, promotes the generation of long “classical” transcripts (with 5′ and 3′ UTRs) but has only a limited impact on alternative splicing in mTEC. Comprehensive assessment of SF expression in mTEC identified a small set of nonpromiscuously expressed SF genes, among which we confirmed RBFOX to be present with AIRE in mTEC nuclei. Using a conditional loss-of-function approach, we show that Rbfox2 promotes mTEC development and regulates the alternative splicing of promiscuously expressed genes. These data indicate that TEC recommission a small number of peripheral SFs, including members of the RBFOX family, to generate a broad but selective representation of the peripheral splice isoform repertoire.
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影响因子：
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