Early myeloid lineage choice is not initiated by random PU.1 to GATA1 protein ratios

Nature. 2016 Jul 14;535(7611):299-302. doi: 10.1038/nature18320.

Abstract

The mechanisms underlying haematopoietic lineage decisions remain disputed. Lineage-affiliated transcription factors with the capacity for lineage reprogramming, positive auto-regulation and mutual inhibition have been described as being expressed in uncommitted cell populations. This led to the assumption that lineage choice is cell-intrinsically initiated and determined by stochastic switches of randomly fluctuating cross-antagonistic transcription factors. However, this hypothesis was developed on the basis of RNA expression data from snapshot and/or population-averaged analyses. Alternative models of lineage choice therefore cannot be excluded. Here we use novel reporter mouse lines and live imaging for continuous single-cell long-term quantification of the transcription factors GATA1 and PU.1 (also known as SPI1). We analyse individual haematopoietic stem cells throughout differentiation into megakaryocytic-erythroid and granulocytic-monocytic lineages. The observed expression dynamics are incompatible with the assumption that stochastic switching between PU.1 and GATA1 precedes and initiates megakaryocytic-erythroid versus granulocytic-monocytic lineage decision-making. Rather, our findings suggest that these transcription factors are only executing and reinforcing lineage choice once made. These results challenge the current prevailing model of early myeloid lineage choice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation*
  • Cell Lineage*
  • Erythrocytes / cytology
  • Feedback, Physiological
  • Female
  • GATA1 Transcription Factor / metabolism*
  • Genes, Reporter
  • Granulocytes / cytology
  • Hematopoiesis
  • Hematopoietic Stem Cells / cytology
  • Male
  • Megakaryocytes / cytology
  • Mice
  • Models, Biological
  • Monocytes / cytology
  • Myeloid Cells / cytology*
  • Proto-Oncogene Proteins / metabolism*
  • Reproducibility of Results
  • Single-Cell Analysis
  • Stochastic Processes
  • Trans-Activators / metabolism*

Substances

  • GATA1 Transcription Factor
  • Gata1 protein, mouse
  • Proto-Oncogene Proteins
  • Trans-Activators
  • proto-oncogene protein Spi-1