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Cell Stem Cell. 2014 Oct 2;15(4):507-22. doi: 10.1016/j.stem.2014.07.005. Epub 2014 Aug 21.

Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis.

Author information

1
Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany.
2
Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
3
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
4
Division of Epigenomics and Cancer Risk Factors, DKFZ, 69120 Heidelberg, Germany.
5
Division of Theoretical Bioinformatics, Department of Bioinformatics and Functional Genomics, DKFZ, 69120 Heidelberg, Germany; Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, 69120 Heidelberg, Germany.
6
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Junior Research Group Experimental Hematology, Division of Stem Cells and Cancer, DKFZ, 69120 Heidelberg, Germany.
7
Division of Epigenomics and Cancer Risk Factors, DKFZ, 69120 Heidelberg, Germany; Division of Theoretical Bioinformatics, Department of Bioinformatics and Functional Genomics, DKFZ, 69120 Heidelberg, Germany; Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, 69120 Heidelberg, Germany.
8
Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; Junior Research Group Stress-induced Activation of Hematopoietic Stem Cells, Division of Stem Cells and Cancer, DKFZ, 69120 Heidelberg, Germany.
9
Division of Theoretical Bioinformatics, Department of Bioinformatics and Functional Genomics, DKFZ, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, 69120 Heidelberg, Germany.
10
Division of Epigenomics and Cancer Risk Factors, DKFZ, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
11
Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ), 69120 Heidelberg, Germany; Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. Electronic address: a.trumpp@dkfz.de.

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.

PMID:
25158935
DOI:
10.1016/j.stem.2014.07.005
[Indexed for MEDLINE]
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