Combinatorial Transcriptional Control in Blood stem/progenitor Cells: Genome-Wide Analysis of Ten Major Transcriptional Regulators

Cell Stem Cell. 2010 Oct 8;7(4):532-44. doi: 10.1016/j.stem.2010.07.016.

Abstract

Combinatorial transcription factor (TF) interactions control cellular phenotypes and, therefore, underpin stem cell formation, maintenance, and differentiation. Here, we report the genome-wide binding patterns and combinatorial interactions for ten key regulators of blood stem/progenitor cells (SCL/TAL1, LYL1, LMO2, GATA2, RUNX1, MEIS1, PU.1, ERG, FLI-1, and GFI1B), thus providing the most comprehensive TF data set for any adult stem/progenitor cell type to date. Genome-wide computational analysis of complex binding patterns, followed by functional validation, revealed the following: first, a previously unrecognized combinatorial interaction between a heptad of TFs (SCL, LYL1, LMO2, GATA2, RUNX1, ERG, and FLI-1). Second, we implicate direct protein-protein interactions between four key regulators (RUNX1, GATA2, SCL, and ERG) in stabilizing complex binding to DNA. Third, Runx1(+/-)::Gata2(+/-) compound heterozygous mice are not viable with severe hematopoietic defects at midgestation. Taken together, this study demonstrates the power of genome-wide analysis in generating novel functional insights into the transcriptional control of stem and progenitor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Gene Expression Regulation / genetics*
  • Genome*
  • Genome-Wide Association Study
  • Mice
  • Stem Cells / metabolism*
  • Transcription Factors / genetics*
  • Transcription, Genetic / genetics*

Substances

  • Transcription Factors

Associated data

  • GEO/GSE22178