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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Nina Cabezas-Wallscheid
  • Daniel Klimmeck
  • Daniel B Lipka
  • Alejandro Reyes
  • Qi Wang
  • Dieter Weichenhan
  • Amelie Lier
  • Lisa von Paleske
  • Simon Renders
  • Peer Wünsche
  • Petra Zeisberger
  • David Brocks
  • Lei Gu
  • Carl Herrmann
  • Simon Haas
  • Marieke A G Essers
  • Benedikt Brors
  • Roland Eils
  • Wolfgang Huber
  • Michael D Milsom
  • Christoph Plass
  • Jeroen Krijgsveld
  • Andreas Trumpp
Organisations
External organisations
  • European Molecular Biology Laboratory Heidelberg
Research areas and keywords

Keywords

  • Adult, Cell Differentiation, Cell Lineage, Cluster Analysis, DNA Methylation, Epigenesis, Genetic, Gene Expression Profiling, Gene Regulatory Networks, Genome, Human, Genomic Imprinting, Hematopoietic Stem Cells, Humans, Molecular Sequence Data, Protein Isoforms, Proteome, RNA, Long Noncoding, Transcription Factors, Transcriptome
Original languageEnglish
Pages (from-to)507-22
Number of pages16
JournalCell Stem Cell
Volume15
Issue number4
Publication statusPublished - 2014 Oct 2
Publication categoryResearch
Peer-reviewedYes