@article{a3c142fd8d3240b8b0d1581381670752,
title = "A CLK3-HMGA2 Alternative Splicing Axis Impacts Human Hematopoietic Stem Cell Molecular Identity throughout Development",
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.",
keywords = "CLK3, HMGA2, RNA-seq, SRSF1, alternative splicing, human hematopoietic stem cells",
author = "Marcella Cesana and Guo, {Michael H.} and Davide Cacchiarelli and Lara Wahlster and Jessica Barragan and Sergei Doulatov and Vo, {Linda T.} and Beatrice Salvatori and Cole Trapnell and Kendell Clement and Patrick Cahan and Tsanov, {Kaloyan M.} and Sousa, {Patricia M.} and Barbara Tazon-Vega and Adriano Bolondi and Giorgi, {Federico M.} and Andrea Califano and Rinn, {John L.} and Alexander Meissner and Hirschhorn, {Joel N.} and Daley, {George Q.}",
note = "Funding Information: We are grateful to Trista North for critical review of the manuscript; Tarjei Mikkelsen, Michael Ziller, and Areum Han for technical assistance and for helpful discussion; Ronald Mathieu and Mahnaz Paktinat at the BCH Flow Cytometry core for sorting; Annamaria Carissimo for assistance with statistical analyses; and Julie Martone and Irene Bozzoni for providing the plasmid for the splicing assay. This work is supported by grants to G.Q.D. from the NIH NIDDK ( R24-DK092760 and U54-DK110805 ) and the NHLBI Progenitor Cell Biology Consortium ( UO1-HL100001 ). G.Q.D. was also supported by the Howard Hughes Medical Institute and is an affiliate of the Broad Institute . Additional support was given to J.N.H. from NIH grant R01DK075787 ; to A.M. from New York Stem Cell Foundation ; to A.C. from NCI Outstanding Investigator Award ( R35 CA197745 ); to A.C., B.S., and F.M.G. from Centers for Cancer Systems Biology ( U54 CA209997 ); and to D.C. from Fondazione Telethon Core Grant . D.C. is an Armenise-Harvard Foundation Career Development Award Investigator and a Rita-Levi Montalcini Program Fellow from MIUR . A.M. is a New York Stem Cell Foundation Robertson Investigator . M.C. was supported by EMBO Long Term Fellowship and Leukemia and Lymphoma Society Fellowship . L.T.V. was supported by the NSF Graduate Research Fellowship . K.M.T. was supported by the HHMI International Student Research Fellowship and the Herchel Smith Graduate Fellowship . Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = apr,
day = "5",
doi = "10.1016/j.stem.2018.03.012",
language = "English (US)",
volume = "22",
pages = "575--588.e7",
journal = "Cell stem cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "4",
}