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

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 d...

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Published in:Cell stem cell 2018-04, Vol.22 (4), p.575-588.e7
Main Authors: Cesana, Marcella, Guo, Michael H., Cacchiarelli, Davide, Wahlster, Lara, Barragan, Jessica, Doulatov, Sergei, Vo, Linda T., Salvatori, Beatrice, Trapnell, Cole, Clement, Kendell, Cahan, Patrick, Tsanov, Kaloyan M., Sousa, Patricia M., Tazon-Vega, Barbara, Bolondi, Adriano, Giorgi, Federico M., Califano, Andrea, Rinn, John L., Meissner, Alexander, Hirschhorn, Joel N., Daley, George Q.
Format: Article
Language:English
Subjects:
alternative splicing
CLK3
HMGA2
human hematopoietic stem cells
RNA-seq
SRSF1
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Summary: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. [Display omitted] •Substantial diversity of human HSC transcriptomes shown at distinct developmental stages•HMGA2 alternative 3′ UTR usage is functional to avoid miRNA-mediated inhibition•CLK3 affects the HMGA2 splicing pattern by promoting exon skipping Human hematopoietic stem cells (HSCs) display substantial transcriptional diversity during development. Here, we investigated the contribution of alternative splicing to 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.
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2018.03.012