A CLK3-HMGA2 Alternative Splicing Axis Impacts Human Hematopoietic Stem Cell Molecular Identity throughout Development.
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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. |
Year of Publication | 2018
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Journal | Cell Stem Cell
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Volume | 22
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Issue | 4
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Pages | 575-588.e7
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Date Published | 2018 04 05
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ISSN | 1875-9777
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DOI | 10.1016/j.stem.2018.03.012
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PubMed ID | 29625070
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PubMed Central ID | PMC5957284
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Grant list | R24 OD017870 / OD / NIH HHS / United States
U54 CA209997 / CA / NCI NIH HHS / United States
P30 DK049216 / DK / NIDDK NIH HHS / United States
R01 DK075787 / DK / NIDDK NIH HHS / United States
U01 HL100001 / HL / NHLBI NIH HHS / United States
S10 OD012351 / OD / NIH HHS / United States
R24 DK092760 / DK / NIDDK NIH HHS / United States
S10 OD021764 / OD / NIH HHS / United States
R35 CA197745 / CA / NCI NIH HHS / United States
HHMI / Howard Hughes Medical Institute / United States
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