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

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.

doi:10.1016/j.stem.2018.03.012

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

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Meissner, Alexander
Dept. of Genome Regulation (Head: Alexander Meissner), Max Planck Institute for Molecular Genetics, Max Planck Society;
Harvard Stem Cell Institute, Cambridge, MA 02138, USA;
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA;
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA;

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Citation

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.

Cite as: https://hdl.handle.net/21.11116/0000-0003-4B7B-0

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.