An important class of intron retention events in human erythroblasts is regulated by cryptic exons proposed to function as splicing decoys

Parra Marilyn; Booth Ben W.; Weiszmann Richard; Yee Brian; Yeo Gene W.; Brown James B.; Celniker Susan E.; Conboy John G.

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An important class of intron retention events in human erythroblasts is regulated by cryptic exons proposed to function as splicing decoys

机译：人红细胞中的一个重要类别的内含子保留事件是通过提出用作剪接诱饵的神秘外显子来调节

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During terminal erythropoiesis, the splicing machinery in differentiating erythroblasts executes a robust intron retention (IR) program that impacts expression of hundreds of genes. We studied IR mechanisms in the SF3B1 splicing factor gene, which expresses similar to 50% of its transcripts in late erythroblasts as a nuclear isoform that retains intron 4. RNA-seq analysis of nonsense-mediated decay (NMD)-inhibited cells revealed previously undescribed splice junctions, rare or not detected in normal cells, that connect constitutive exons 4 and 5 to highly conserved cryptic cassette exons within the intron. Minigene splicing reporter assays showed that these cassettes promote IR. Genome-wide analysis of splice junction reads demonstrated that cryptic noncoding cassettes are much more common in large (1 kb) retained introns than they are in small retained introns or in nonretained introns. Functional assays showed that heterologous cassettes can promote retention of intron 4 in the SF3B1 splicing reporter. Although many of these cryptic exons were spliced inefficiently, they exhibited substantial binding of U2AF1 and U2AF2 adjacent to their splice acceptor sites. We propose that these exons function as decoys that engage the intron-terminal splice sites, thereby blocking cross-intron interactions required for excision. Developmental regulation of decoy function underlies a major component of the erythroblast IR program.

机译：在末端红细胞凋亡期间，分化红细胞细胞的拼接机械执行强大的内含子保留（IR）程序，影响数百个基因的表达。我们研究了SF3B1剪接因子基因中的IR机制，其表达与晚期红细胞中的50％的成绩单中，作为保留内含子4. RNA-SEQ分析的废话介导的衰减（NMD） - 抑制的细胞透露前所未有的细胞剪接结，在正常细胞中罕见或未检测到，将本构显子4和5连接到内含子内的高度保守的隐蔽盒外显子。小烯剪接报告结果显示，这些盒子促进IR。对接头结的基因组分析读取的读取表明，密码非编码盒的大（＆ 1kb）保留内含子比在小保留内含子或非托管内含子中更常见。功能测定表明，异源盒可以促进在SF3B1剪接报告中的内含子4的保留。虽然许多这些神秘的外显子性均低效剪接，但它们表现出U2AF1和U2AF2与其接头受体位点相邻的大致结合。我们建议这些外显子用作与内含子接头位点接合的诱饵，从而阻止切除所需的交叉内含子相互作用。诱饵功能的发育调节是红细胞红外程序的主要组成部分。

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《RNA》 |2018年第9期|共11页
作者
Parra Marilyn; Booth Ben W.; Weiszmann Richard; Yee Brian; Yeo Gene W.; Brown James B.; Celniker Susan E.; Conboy John G.;
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作者单位

Lawrence Berkeley Natl Lab Biol Syst &

Engn Div Berkeley CA 94720 USA;

Lawrence Berkeley Natl Lab Biol Syst &

Engn Div Berkeley CA 94720 USA;

Lawrence Berkeley Natl Lab Biol Syst &

Engn Div Berkeley CA 94720 USA;

Univ Calif San Diego Dept Cellular &

Mol Med La Jolla CA 92037 USA;

Univ Calif San Diego Dept Cellular &

Mol Med La Jolla CA 92037 USA;

Lawrence Berkeley Natl Lab Environm Genom &

Syst Biol Berkeley CA 94720 USA;

Lawrence Berkeley Natl Lab Biol Syst &

Engn Div Berkeley CA 94720 USA;

Lawrence Berkeley Natl Lab Biol Syst &

Engn Div Berkeley CA 94720 USA;

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原文格式 PDF
正文语种 eng
中图分类生物化学;
关键词
SF3B1; alternative splicing; intron retention;

机译：SF3B1;替代拼接;内含子保留;

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专利

1. An important class of intron retention events in human erythroblasts is regulated by cryptic exons proposed to function as splicing decoys [J] . Parra Marilyn, Booth Ben W., Weiszmann Richard, RNA . 2018,第9期

机译：人红细胞中的一个重要类别的内含子保留事件是通过提出用作剪接诱饵的神秘外显子来调节
2. A 6-bp deletion at the splice donor site of the first intron resulted in aberrant splicing using a cryptic splice site within exon 1 in a patient with succinyl-CoA: 3-Ketoacid CoA transferase (SCOT) deficiency. [J] . Fukao T, Sakurai S, Rolland MO, Molecular genetics and metabolism . 2006,第3期

机译：在患有琥珀酰辅酶A：3-酮酸辅酶A转移酶（SCOT）缺乏症的患者中，第一个内含子的剪接供体位点6 bp缺失导致使用外显子1内的隐蔽剪接位点进行异常剪接。
3. A mutation (IVS8+0.6kbdelTC) creating a new donor splice site activates a cryptic exon in an Alu-element in intron 8 of the human beta-glucuronidase gene. [J] . Vervoort R, Gitzelmann R, Lissens W, Human Genetics . 1998,第6期

机译：产生新的供体剪接位点的突变（IVS8 + 0.6kbdelTC）激活了人类β-葡萄糖醛酸苷酶基因内含子8中Alu元件中的一个隐性外显子。
4. Intrinsic Splicing Profile of Human Genes Undergoing Simple Cassette Exon Events [C] . Andigoni Malousi, Vassilis Koutkias, Sofia Kouidou, Biological and Medical Data Analysis; Lecture Notes in Bioinformatics; 4345 . 2006

机译：简单盒式外显子事件后人类基因的内在剪接配置文件
5. Exosomal proteome changes induced by human tau expression are modulated by the presence of the microtubule-binding domain and alternatively spliced exons 2-3 in SH-SY5Y neuroblastoma cells [D] . Aladwan, Mohammad Mahmoud. 2017

机译：SH-SY5Y神经母细胞瘤细胞中微管结合结构域的存在和其他剪接的外显子2-3的存在可以调节人tau表达诱导的外泌体蛋白质组变化
6. An important class of intron retention events in human erythroblasts is regulated by cryptic exons proposed to function as splicing decoys [O] . Marilyn Parra, Ben W. Booth, Richard Weiszmann, 2018

机译：人类成红细胞中一类重要的内含子保留事件受拟用作剪接诱饵的隐性外显子调控
7. Antisense targeting of decoy exons can reduce intron retention and increase protein expression in human erythroblasts [O] . Marilyn Parra, Weiguo Zhang, Jonathan Vu, 2020

机译：对诱饵外显子的反义靶向可以减少内含子保留和增加人红细胞中的蛋白质表达

An important class of intron retention events in human erythroblasts is regulated by cryptic exons proposed to function as splicing decoys

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