A CLK3-HMGA2 Alternative Splicing Axis Impacts Human Hematopoietic Stem Cell Molecular Identity throughout Development.
A CLK3-HMGA2 Alternative Splicing Axis Impacts Human Hematopoietic Stem Cell Molecular Identity throughout Development.
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DOI：
10.1016/j.stem.2018.03.012
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发表时间：
2018-04-05
期刊：
影响因子：
23.9
通讯作者：
Daley GQ
中科院分区：
文献类型：
--
作者：
Cesana M;Guo MH;Cacchiarelli D;Wahlster L;Barragan J;Doulatov S;Vo LT;Salvatori B;Trapnell C;Clement K;Cahan P;Tsanov KM;Sousa PM;Tazon-Vega B;Bolondi A;Giorgi FM;Califano A;Rinn JL;Meissner A;Hirschhorn JN;Daley GQ
虽然在成人造血分化过程中基因表达动态已被广泛编录，但对人类造血干细胞（hsc）在发育过程中的转录组多样性知之甚少。为了表征造血干细胞在发育过程中的转录和转录后变化，我们利用高通量基因组方法来分析mirna、lincrna和mrna。我们的研究结果表明造血干细胞在关键的造血调节因子中表现出不同的剪接模式。通过对其中一种调节因子HMGA2的剪接动力学和功能的详细分析，发现了一种逃避mirna介导靶向的替代异构体。我们进一步确定了剪接激酶CLK3，通过调节HMGA2剪接，在let-7 miRNA水平增加的情况下保持HMGA2的功能，描绘了CLK3和HMGA2如何形成影响HSC发育过程中特性的功能轴。总的来说，我们的研究强调了选择性剪接和mirna介导的转录后调控影响人造血干细胞的分子特性和阶段特异性发育特征的分子机制。人类造血干细胞（hsc）在发育过程中显示出大量的转录多样性。在这里，我们通过分析一个关键的造血调节因子HMGA2的动力学来研究选择性剪接对这种多样性的贡献。接下来，我们发现CLK3通过调节HMGA2的剪接模式，加强hsc特异性程序。
While gene expression dynamics have been extensively catalogued during hematopoietic differentiation in the adult, less is known about transcriptome diversity of human hematopoietic stem cells (HSCs) during development. To characterize transcriptional and post-transcriptional changes in HSCs during development, we leveraged high-throughput genomic approaches to profile miRNAs, lincRNAs, and mRNAs. Our findings indicate that HSCs manifest distinct alternative splicing patterns in key hematopoietic regulators. Detailed analysis of the splicing dynamics and function of one such regulator, HMGA2, identified an alternative isoform that escapes miRNA-mediated targeting. We further identified the splicing kinase CLK3 that, by regulating HMGA2 splicing, preserves HMGA2 function in the setting of an increase in let-7 miRNA levels, delineating how CLK3 and HMGA2 form a functional axis that influences HSC properties during development. Collectively, our study highlights molecular mechanisms by which alternative splicing and miRNA-mediated post-transcriptional regulation impact the molecular identity and stage-specific developmental features of human HSCs. Human hematopoietic stem cells (HSCs) display substantial transcriptional diversity during development. Here, we investigated the contribution of alternative splicing on such diversity by analyzing the dynamics of a key hematopoietic regulator, HMGA2. Next, we showed that CLK3, by regulating the splicing pattern of HMGA2, reinforces an HSC-specific program.
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影响因子：
64.5
作者：
Bernitz, Jeffrey M.;Kim, Huen Suk;MacArthur, Ben;Sieburg, Hans;Moore, Kateri
通讯作者：
Moore, Kateri
影响因子：
23.9
作者：
Doulatov, Sergei;Vo, Linda T.;Chou, Stephanie S.;Kim, Peter G.;Arora, Natasha;Li, Hu;Hadland, Brandon K.;Bernstein, Irwin D.;Collins, James J.;Zon, Leonard I.;Daley, George Q.
通讯作者：
Daley, George Q.
影响因子：
64.8
作者：
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影响因子：
7
作者：
Harrow J;Frankish A;Gonzalez JM;Tapanari E;Diekhans M;Kokocinski F;Aken BL;Barrell D;Zadissa A;Searle S;Barnes I;Bignell A;Boychenko V;Hunt T;Kay M;Mukherjee G;Rajan J;Despacio-Reyes G;Saunders G;Steward C;Harte R;Lin M;Howald C;Tanzer A;Derrien T;Chrast J;Walters N;Balasubramanian S;Pei B;Tress M;Rodriguez JM;Ezkurdia I;van Baren J;Brent M;Haussler D;Kellis M;Valencia A;Reymond A;Gerstein M;Guigó R;Hubbard TJ
通讯作者：
Hubbard TJ
影响因子：
4.5
作者：
Colombo DF;Burger L;Baubec T;Schübeler D
通讯作者：
Schübeler D