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Identification of Regulatory Networks in HSCs and Their Immediate Progeny via Integrated Proteome, Transcriptome, and DNA Methylome Analysis

Cabezas-Wallscheid, Nina, Klimmeck, Daniel, Hansson, Jenny, Lipka, Daniel B., Reyes, Alejandro, Wang, Qi, Weichenhan, Dieter, Lier, Amelie, von Paleske, Lisa, Renders, Simon, Wünsche, 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·2014·Cell Stem Cell
DOI 10.1016/j.stem.2014.07.005
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Abstract

In this study, we present integrated quantitative proteome, transcriptome, and methylome analyses of hematopoietic stem cells (HSCs) and four multipotent progenitor (MPP) populations. From the characterization of more than 6,000 proteins, 27,000 transcripts, and 15,000 differentially methylated regions (DMRs), we identified coordinated changes associated with early differentiation steps. DMRs show continuous gain or loss of methylation during differentiation, and the overall change in DNA methylation correlates inversely with gene expression at key loci. Our data reveal the differential expression landscape of 493 transcription factors and 682 lncRNAs and highlight specific expression clusters operating in HSCs. We also found an unexpectedly dynamic pattern of transcript isoform regulation, suggesting a critical regulatory role during HSC differentiation, and a cell cycle/DNA repair signature associated with multipotency in MPP2 cells. This study provides a comprehensive genome-wide resource for the functional exploration of molecular, cellular, and epigenetic regulation at the top of the hematopoietic hierarchy.

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Metadata

Authors
Cabezas-Wallscheid, N., Klimmeck, D., Hansson, J., Lipka, D. B., Reyes, A., Wang, Q., Weichenhan, D., Lier, A., von Paleske, L., Renders, S., Wünsche, P., Zeisberger, P., Brocks, D., Gu, L., Herrmann, C., Haas, S., Essers, M. A. G., Brors, B., Eils, R., Huber, W., Milsom, M. D., Plass, C., Krijgsveld, J., & Trumpp, A.
Venue
Cell Stem Cell
Publisher
Elsevier BV
Published
2014-10
Volume
15
Issue
4
Pages
507-522
ISSN
1934-5909
DOI
10.1016/j.stem.2014.07.005
Cited by
589
References
15
Language
en
Licence
Funders
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek
  • Deutsches Krebsforschungszentrum
  • Seventh Framework Programme
  • Deutsche Forschungsgemeinschaft (SP1463)
  • Bundesministerium für Bildung und Forschung

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