Computational promoter modeling identifies the modes of transcriptional regulation in hematopoietic stem cells

PLoS One. 2014 Apr 7;9(4):e93853. doi: 10.1371/journal.pone.0093853. eCollection 2014.

Abstract

Extrinsic and intrinsic regulators are responsible for the tight control of hematopoietic stem cells (HSCs), which differentiate into all blood cell lineages. To understand the fundamental basis of HSC biology, we focused on differentially expressed genes (DEGs) in long-term and short-term HSCs, which are closely related in terms of cell development but substantially differ in their stem cell capacity. To analyze the transcriptional regulation of the DEGs identified in the novel transcriptome profiles obtained by our RNA-seq analysis, we developed a computational method to model the linear relationship between gene expression and the features of putative regulatory elements. The transcriptional regulation modes characterized here suggest the importance of transcription factors (TFs) that are expressed at steady state or at low levels. Remarkably, we found that 24 differentially expressed TFs targeting 21 putative TF-binding sites contributed significantly to transcriptional regulation. These TFs tended to be modulated by other nondifferentially expressed TFs, suggesting that HSCs can achieve flexible and rapid responses via the control of nondifferentially expressed TFs through a highly complex regulatory network. Our novel transcriptome profiles and new method are powerful tools for studying the mechanistic basis of cell fate decisions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Lineage / genetics
  • Computer Simulation
  • Databases, Genetic
  • Gene Expression Regulation*
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Models, Genetic*
  • Promoter Regions, Genetic*
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Transcriptome*

Substances

  • Transcription Factors

Grant support

This work was supported by Research on Applying Health Technology, Health and Labour Sciences by the Ministry of Health, Labour and Welfare, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.