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

被引：44

作者：

Cesana, Marcella ^{[1
,2
,3
,4
]}

Guo, Michael H. ^{[5
,6
,7
,8
]}

Cacchiarelli, Davide ^{[4
,5
,9
,10
,11
]}

Wahlster, Lara ^{[1
,2
,3
,4
]}

Barragan, Jessica ^{[1
,2
,3
,4
]}

Doulatov, Sergei ^{[12
]}

Vo, Linda T. ^{[1
,2
,3
,4
]}

Salvatori, Beatrice ^{[13
]}

Trapnell, Cole ^{[14
]}

Clement, Kendell ^{[4
,5
,9
]}

Cahan, Patrick ^{[15
]}

Tsanov, Kaloyan M. ^{[1
,2
,3
,4
]}

Sousa, Patricia M. ^{[1
,2
,3
,4
]}

Tazon-Vega, Barbara ^{[4
,5
,9
]}

Bolondi, Adriano ^{[1
,2
]}

Giorgi, Federico M. ^{[13
]}

Califano, Andrea ^{[13
,16
,17
]}

Rinn, John L. ^{[4
,5
,9
,18
]}

Meissner, Alexander ^{[4
,5
,9
,19
]}

Hirschhorn, Joel N. ^{[5
,6
,7
,8
]}

Daley, George Q. ^{[1
,2
,3
,4
]}

机构：

[1] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Div Hematol Oncol, Stem Cell Program, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Boston, MA 02115 USA

[3] Harvard Med Sch, Harvard Stem Cell Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[4] Harvard Stem Cell Inst, Cambridge, MA 02138 USA

[5] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[6] Boston Childrens Hosp, Div Endocrinol, Boston, MA 02115 USA

[7] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA 02115 USA

[8] Harvard Med Sch, Dept Genet, Boston, MA 02115 USA

[9] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[10] Armenise Harvard Lab Integrat Genom, Telethon Inst Genet & Med TIGEM, I-80078 Pozzuoli, Italy

[11] Univ Naples Federico II, Dept Translat Med, I-80131 Naples, Italy

[12] Univ Washington, Div Hematol, Seattle, WA 98195 USA

[13] Columbia Univ, Dept Syst Biol, New York, NY 10032 USA

[14] Univ Washington, Dept Genome Sci, Seattle, WA 98115 USA

[15] Johns Hopkins Univ, Inst Cell Engn, Dept Biomed Engn, Sch Med, Baltimore, MD 21205 USA

[16] Columbia Univ, JP Sulzberger Columbia Genome Ctr, Herbert Irving Comprehens Canc Ctr, Dept Biomed Informat, New York, NY 10032 USA

[17] Columbia Univ, JP Sulzberger Columbia Genome Ctr, Herbert Irving Comprehens Canc Ctr, Dept Biochem & Mol Biophys, New York, NY 10032 USA

[18] Univ Colorado Boulder Biofrontiers, Boulder, CO 80301 USA

[19] Max Planck Inst Mol Genet, D-14195 Berlin, Germany

来源：

CELL STEM CELL | 2018年 / 22卷 / 04期

关键词：

SELF-RENEWAL; HMGI-C; GENE; PHOSPHORYLATION; REARRANGEMENTS; ANNOTATION; PATHWAY; GROWTH; LET-7; FETAL;

D O I：

10.1016/j.stem.2018.03.012

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

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 high-lights molecular mechanisms by which alternative splicing and miRNA-mediated post-transcriptional regulation impact the molecular identity and stage-specific developmental features of human HSCs.

引用

页码：575 / +

页数：21

共 60 条

[1] Predicting effective microRNA target sites in mammalian mRNAs [J].

Agarwal, Vikram ;

Bell, George W. ;

Nam, Jin-Wu ;

Bartel, David P. .

ELIFE, 2015, 4

[2] Release of SR Proteins from CLK1 by SRPK1: A Symbiotic Kinase System for Phosphorylation Control of Pre-mRNA Splicing [J].

Aubol, Brandon E. ;

Wu, Guowei ;

Keshwani, Malik M. ;

Movassat, Maliheh ;

Fattet, Laurent ;

Hertel, Klemens J. ;

Fu, Xiang-Dong ;

Adams, Joseph A. .

MOLECULAR CELL, 2016, 63 (02) :218-228

[3] Hierarchical organization of fetal and adult hematopoietic stem cells [J].

Babovic, Sonja ;

Eaves, Connie J. .

EXPERIMENTAL CELL RESEARCH, 2014, 329 (02) :185-191

[4] Hematopoietic Stem Cells Count and Remember Self-Renewal Divisions [J].

Bernitz, Jeffrey M. ;

Kim, Huen Suk ;

MacArthur, Ben ;

Sieburg, Hans ;

Moore, Kateri .

CELL, 2016, 167 (05) :1296-+

[5] Identification of Regulatory Networks in HSCs and Their Immediate Progeny via Integrated Proteome, Transcriptome, and DNA Methylome Analysis [J].

Cabezas-Wallscheid, Nina ;

Klimmeck, Daniel ;

Hansson, Jenny ;

Lipka, Daniel B. ;

Reyes, Alejandro ;

Wang, Qi ;

Weichenhan, Dieter ;

Lier, Amelie ;

von Paleske, Lisa ;

Renders, Simon ;

Wuensche, Peer ;

Zeisberger, Petra ;

Brocks, David ;

Gu, Lei ;

Herrmann, Carl ;

Haas, Simon ;

Essers, Marieke A. G. ;

Brors, Benedikt ;

Eils, Roland ;

Huber, Wolfgang ;

Milsom, Michael D. ;

Plass, Christoph ;

Krijgsveld, Jeroen ;

Trumpp, Andreas .

CELL STEM CELL, 2014, 15 (04) :507-522

[6] Integrative annotation of human large intergenic noncoding RNAs reveals global properties and specific subclasses [J].

Cabili, Moran N. ;

Trapnell, Cole ;

Goff, Loyal ;

Koziol, Magdalena ;

Tazon-Vega, Barbara ;

Regev, Aviv ;

Rinn, John L. .

GENES & DEVELOPMENT, 2011, 25 (18) :1915-1927

[7] Integrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency [J].

Cacchiarelli, Davide ;

Trapnell, Cole ;

Ziller, Michael J. ;

Soumillon, Magali ;

Cesana, Marcella ;

Karnik, Rahul ;

Donaghey, Julie ;

Smith, Zachary D. ;

Ratanasirintrawoot, Sutheera ;

Zhang, Xiaolan ;

Sui, Shannan J. Ho ;

Wu, Zhaoting ;

Akopian, Veronika ;

Gifford, Casey A. ;

Doench, John ;

Rinn, John L. ;

Daley, George Q. ;

Meissner, Alexander ;

Lander, Eric S. ;

Mikkelsen, Tarjei S. .

CELL, 2015, 162 (02) :412-424

[8] Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia [J].

Cavazzana-Calvo, Marina ;

Payen, Emmanuel ;

Negre, Olivier ;

Wang, Gary ;

Hehir, Kathleen ;

Fusil, Floriane ;

Down, Julian ;

Denaro, Maria ;

Brady, Troy ;

Westerman, Karen ;

Cavallesco, Resy ;

Gillet-Legrand, Beatrix ;

Caccavelli, Laure ;

Sgarra, Riccardo ;

Maouche-Chretien, Leila ;

Bernaudin, Francoise ;

Girot, Robert ;

Dorazio, Ronald ;

Mulder, Geert-Jan ;

Polack, Axel ;

Bank, Arthur ;

Soulier, Jean ;

Larghero, Jerome ;

Kabbara, Nabil ;

Dalle, Bruno ;

Gourmel, Bernard ;

Socie, Gerard ;

Chretien, Stany ;

Cartier, Nathalie ;

Aubourg, Patrick ;

Fischer, Alain ;

Cornetta, Kenneth ;

Galacteros, Frederic ;

Beuzard, Yves ;

Gluckman, Eliane ;

Bushman, Frederick ;

Hacein-Bey-Abina, Salima ;

Leboulch, Philippe .

NATURE, 2010, 467 (7313) :318-U94

[9] Cytokines and BMP-4 promote hematopoietic differentiation of human embryonic stem cells [J].

Chadwick, K ;

Wang, LS ;

Li, L ;

Menendez, P ;

Murdoch, B ;

Rouleau, A ;

Bhatia, M .

BLOOD, 2003, 102 (03) :906-915

[10]

Chambers J. M., 1991, STAT MODELS S

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