title: Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis.
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.
authors.affiliation: 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.
authors.forename: Nina
authors.initials: N
authors.lastname: Cabezas-Wallscheid
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Klimmeck
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Hansson
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, DKFZ, 69120 Heidelberg, Germany.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Lipka
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Reyes
authors.affiliation: 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.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, DKFZ, 69120 Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.affiliation: 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.
authors.forename: Amelie
authors.initials: A
authors.lastname: Lier
authors.affiliation: 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.
authors.forename: Lisa
authors.initials: L
authors.lastname: von Paleske
authors.affiliation: 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.
authors.forename: Simon
authors.initials: S
authors.lastname: Renders
authors.affiliation: 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.
authors.forename: Peer
authors.initials: P
authors.lastname: Wünsche
authors.affiliation: 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.
authors.forename: Petra
authors.initials: P
authors.lastname: Zeisberger
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, DKFZ, 69120 Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Brocks
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: 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.
authors.forename: Carl
authors.initials: C
authors.lastname: Herrmann
authors.affiliation: 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.
authors.forename: Simon
authors.initials: S
authors.lastname: Haas
authors.affiliation: 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.
authors.forename: Marieke A G
authors.initials: MAG
authors.lastname: Essers
authors.affiliation: 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.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: 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.
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Huber
authors.affiliation: 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.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Milsom
authors.affiliation: Division of Epigenomics and Cancer Risk Factors, DKFZ, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Krijgsveld
authors.affiliation: 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.
authors.forename: Andreas
authors.initials: A
authors.lastname: Trumpp
mesh_terms: D000328:Adult; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D016000:Cluster Analysis; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D015894:Genome, Human / Q000235:genetics; D018392:Genomic Imprinting; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D020543:Proteome / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics*
chemical_list: D020033:Protein Isoforms; D020543:Proteome; D062085:RNA, Long Noncoding; D014157:Transcription Factors