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

Marcella Cesana, Michael H. Guo, Davide Cacchiarelli, Lara Wahlster, Jessica Barragan, Sergei Doulatov, Linda T. Vo, Beatrice Salvatori, Cole Trapnell, Kendell Clement, Patrick Cahan, Kaloyan M. Tsanov, Patricia M. Sousa, Barbara Tazon-Vega, Adriano Bolondi, Federico M. Giorgi, Andrea Califano, John L. Rinn, Alexander Meissner, Joel N. HirschhornGeorge Q. Daley

Research output: Contribution to journalArticlepeer-review

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. 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.

Original languageEnglish (US)
Pages (from-to)575-588.e7
JournalCell stem cell
Volume22
Issue number4
DOIs
StatePublished - Apr 5 2018

Keywords

  • CLK3
  • HMGA2
  • RNA-seq
  • SRSF1
  • alternative splicing
  • human hematopoietic stem cells

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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