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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 LU ; Lipka, Daniel B; Reyes, Alejandro; Wang, Qi; Weichenhan, Dieter; Lier, Amelie; von Paleske, Lisa and Renders, Simon, et al. (2014) In Cell Stem Cell 15(4). p.22-507
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... (More)

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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@misc{f8bcd183-078a-47bc-95e2-e120e4a2365e,
  abstract     = {<p>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.</p>},
  author       = {Cabezas-Wallscheid, Nina and Klimmeck, Daniel and Hansson, Jenny and Lipka, Daniel B and Reyes, Alejandro and Wang, Qi and Weichenhan, Dieter and Lier, Amelie and von Paleske, Lisa and Renders, Simon and Wünsche, Peer and Zeisberger, Petra and Brocks, David and Gu, Lei and Herrmann, Carl and Haas, Simon and Essers, Marieke A G and Brors, Benedikt and Eils, Roland and Huber, Wolfgang and Milsom, Michael D and Plass, Christoph and Krijgsveld, Jeroen and Trumpp, Andreas},
  issn         = {1934-5909},
  keyword      = {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},
  language     = {eng},
  month        = {10},
  number       = {4},
  pages        = {22--507},
  publisher    = {ARRAY(0x9bbdec0)},
  series       = {Cell Stem Cell},
  title        = {Identification of regulatory networks in HSCs and their immediate progeny via integrated proteome, transcriptome, and DNA methylome analysis},
  url          = {http://dx.doi.org/10.1016/j.stem.2014.07.005},
  volume       = {15},
  year         = {2014},
}