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Cell Stem Cell. 2018 Apr 5;22(4):575-588.e7. doi: 10.1016/j.stem.2018.03.012.

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

Author information

1
Stem Cell Program, Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
2
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Division of Endocrinology, Boston Children's Hospital, Boston, MA 02115, USA; Center for Basic and Translational Obesity Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
3
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; Telethon Institute of Genetics and Medicine (TIGEM), Armenise/Harvard Laboratory of Integrative Genomics, Pozzuoli 80078, Italy; Department of Translational Medicine, University of Naples "Federico II", Naples 80131, Italy.
4
Division of Hematology, University of Washington, Seattle, WA 98195, USA.
5
Department of Systems Biology, Columbia University, New York, NY 10032, USA.
6
Department of Genome Sciences, University of Washington, Seattle, WA 98115, USA.
7
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.
8
Department of Biomedical Engineering, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
9
Stem Cell Program, Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02115, USA.
10
Department of Systems Biology, Columbia University, New York, NY 10032, USA; Departments of Biomedical Informatics, Biochemistry and Molecular Biophysics, JP Sulzberger Columbia Genome Center, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
11
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; University of Colorado Boulder Biofrontiers, Boulder, CO 80301, USA.
12
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; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
13
Stem Cell Program, Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital and Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: george.daley@childrens.harvard.edu.

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.

KEYWORDS:

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

PMID:
29625070
PMCID:
PMC5957284
DOI:
10.1016/j.stem.2018.03.012
[Indexed for MEDLINE]
Free PMC Article

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