ArticleCell stem cell2018
A CLK3-HMGA2 Alternative Splicing Axis Impacts Human Hematopoietic Stem Cell Molecular Identity throughout Development.
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Article in Cell stem cell, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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44citing papers in PubMed
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44 citing papers in PubMed, 71 citations in OpenAlex.
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- Dynamic activity of Erg promotes maturation of the hematopoietic system.Blood advances · 2026Article
- Oncogenic DEAD-box ATPase DDX41 establishes transcript ensembles via CLK3-dependent and -independent mechanisms.Nature communications · 2025Article
- HMGA2 Attenuates Tendon Stem/Progenitor Cell Senescence Via PI3K/AKT-Mediated Mitophagy Activation and SASP Suppression.Stem cell reviews and reports · 2025Article
- mRNA Isoforms and Variants in Health and Disease.International journal of molecular sciences · 2025Review
- Systematic identification of minor histocompatibility antigens predicts outcomes of allogeneic hematopoietic cell transplantation.Nature biotechnology · 2025Article
- Targeting RNA splicing modulation: new perspectives for anticancer strategy?Journal of experimental & clinical cancer research : CR · 2025Review
- 3' UTR-truncated HMGA2 promotes erythroblasts production from human embryonic stem cells.Stem cells translational medicine · 2025Article
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- Gene expression networks involved in multiple cellular programs coexist in individual hepatocellular cancer cells.Heliyon · 2023Article
- Childhood hematopoietic stem cells constitute the permissive window for RUNX1-ETO leukemogenesis.International journal of hematology · 2023Review
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Authors and funding
21 authors at 10 institutions in 3 countries.
Marcella CesanaStem 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.
Michael H GuoBroad 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.
Davide CacchiarelliHarvard 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.
Lara WahlsterStem 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.
Jessica BarraganStem 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.
Sergei DoulatovDivision of Hematology, University of Washington, Seattle, WA 98195, USA.
Linda T VoStem 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.
Beatrice SalvatoriDepartment of Systems Biology, Columbia University, New York, NY 10032, USA.
Cole TrapnellDepartment of Genome Sciences, University of Washington, Seattle, WA 98115, USA.
Kendell ClementHarvard 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.
Patrick CahanDepartment of Biomedical Engineering, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Kaloyan M TsanovStem 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.
Patricia M SousaStem 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.
Barbara Tazon-VegaHarvard 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.
Adriano BolondiStem 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.
Federico M GiorgiDepartment of Systems Biology, Columbia University, New York, NY 10032, USA.
Andrea CalifanoDepartment 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.
John L RinnHarvard 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.
Alexander MeissnerHarvard 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.
Joel N HirschhornBroad 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.
George Q DaleyStem 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.
Harvard University · USHarvard Stem Cell Institute · USBoston Children's Hospital · USBroad Institute · USColumbia University · USDana-Farber Cancer Institute · USUniversity of Washington · USJohns Hopkins University · USNew York Genome Center · USTelethon Institute Of Genetics And Medicine · IT
Funding
CORE--ZEBRAFISHP30DK049216 · NIDDK · CHILDREN'S HOSPITAL BOSTON · PI ZHOU, YI · 1999 to 2015
$14.3MCell Interactions in the Inflamed Intestinal MucosaR01DK075787 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI JOEL N HIRSCHHORN · 2007 to 2026
$13.1MPredicting Cancer Cell Response to Endogenous and Exogenous Perturbations at the Single Cell LevelR35CA197745 · NCI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI ANDREA CALIFANO · 2015 to 2026
$11.5MSystematic pharmacological targeting of the core mechanisms responsible for maintaining cancer cell stateU54CA209997 · NCI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI CALIFANO, ANDREA, HONIG, BARRY H · 2016 to 2021
$10.9MCustomized stem cells for clinical application in blood disordersR24DK092760 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI COLLINS, JAMES J, DALEY, GEORGE Q · 2011 to 2018
$10.7MHuman Pluripotent Stem Cell and Progenitor Models of Cardiac and Blood DiseasesU01HL100001 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI DALEY, GEORGE Q, ORKIN, STUART H · 2009 to 2015
$8.9MA Community Zebrafish Resource for Modeling GWAS BiologyR24OD017870 · OD · BRIGHAM AND WOMEN'S HOSPITAL · PI GOESSLING, WOLFRAM, MACRAE, CALUM A. · 2014 to 2021
$6.3MSystematic Identification and Pharmacological Targeting of Tumor Dependencies for Precision Cancer MedicineU01CA217858 · NCI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI CALIFANO, ANDREA · 2017 to 2021
$6.1MHigh-performance compute cluster for biomedical computingS10OD012351 · OD · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI CALIFANO, ANDREA · 2012 to 2012
$2.0MStorage System for High Performance ComputingS10OD021764 · OD · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI CALIFANO, ANDREA · 2016 to 2016
$600kHoward Hughes Medical InstituteNCI NIH HHS R35 CA197745NCI NIH HHS U01 CA217858NCI NIH HHS U54 CA209997NHLBI NIH HHS U01 HL100001NIDDK NIH HHS P30 DK049216NIDDK NIH HHS R01 DK075787NIDDK NIH HHS R24 DK092760NIH HHS R24 OD017870NIH HHS S10 OD012351NIH HHS S10 OD021764
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.
Indexed as
Alternative SplicingHematopoietic Stem CellsHMGA2 ProteinHumansProtein Serine-Threonine KinasesProtein-Tyrosine KinasesRNA, MessengerRNA Processing, Post-TranscriptionalClk dual-specificity kinasesHMGA2 ProteinHMGA2 protein, humanProtein Serine-Threonine KinasesProtein-Tyrosine KinasesRNA, Messengeralternative splicingCLK3HMGA2human hematopoietic stem cellsRNA-seqSRSF1
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