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  A CLK3-HMGA2 Alternative Splicing Axis Impacts Human Hematopoietic Stem Cell Molecular Identity throughout Development

Cesana, M., Guo, M. H., Cacchiarelli, D., Wahlster, L., Barragan, J., Doulatov, S., et al. (2018). A CLK3-HMGA2 Alternative Splicing Axis Impacts Human Hematopoietic Stem Cell Molecular Identity throughout Development. Cell Stem Cell, 22(4): e7, pp. 575-588. doi:10.1016/j.stem.2018.03.012.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-4B7B-0 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-4B7C-F
Genre: Journal Article

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 Creators:
Cesana, Marcella, Author
Guo, Michael H. , Author
Cacchiarelli, Davide , Author
Wahlster, Lara , Author
Barragan, Jessica , Author
Doulatov, Sergei , Author
Vo, Linda T. , Author
Salvatori, Beatrice , Author
Trapnell, Cole , Author
Clement, Kendell , Author
Cahan, Patrick , Author
Tsanov, Kaloyan M. , Author
Sousa, Patricia M. , Author
Tazon-Vega, Barbara , Author
Bolondi, Adriano, Author
Giorgi, Federico M. , Author
Califano, Andrea , Author
Rinn, John L. , Author
Meissner, Alexander1, 2, 3, 4, Author              
Hirschhorn, Joel N. , Author
Daley, George Q. , Author more..
Affiliations:
1Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2379694              
2Harvard Stem Cell Institute, Cambridge, MA 02138, USA, ou_persistent22              
3Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, ou_persistent22              
4Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA, ou_persistent22              

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Free keywords: CLK3; HMGA2; RNA-seq; SRSF1; alternative splicing; human hematopoietic stem cells
 Abstract: While gene expression dynamics have been extensively cataloged 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.

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Language(s): eng - English
 Dates: 2018-03-142018-04-05
 Publication Status: Published online
 Pages: -
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 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1016/j.stem.2018.03.012
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Title: Cell Stem Cell
Source Genre: Journal
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Publ. Info: Cambridge, Mass. : Cell Press
Pages: 14 Volume / Issue: 22 (4) Sequence Number: e7 Start / End Page: 575 - 588 Identifier: ISSN: 1934-5909
CoNE: https://pure.mpg.de/cone/journals/resource/1934-5909