Transcriptome-wide Noise Controls Lineage Choice in Mammalian Progenitor Cells

Nature. 2008 May 22;453(7194):544-7. doi: 10.1038/nature06965.

Abstract

Phenotypic cell-to-cell variability within clonal populations may be a manifestation of 'gene expression noise', or it may reflect stable phenotypic variants. Such 'non-genetic cell individuality' can arise from the slow fluctuations of protein levels in mammalian cells. These fluctuations produce persistent cell individuality, thereby rendering a clonal population heterogeneous. However, it remains unknown whether this heterogeneity may account for the stochasticity of cell fate decisions in stem cells. Here we show that in clonal populations of mouse haematopoietic progenitor cells, spontaneous 'outlier' cells with either extremely high or low expression levels of the stem cell marker Sca-1 (also known as Ly6a; ref. 9) reconstitute the parental distribution of Sca-1 but do so only after more than one week. This slow relaxation is described by a gaussian mixture model that incorporates noise-driven transitions between discrete subpopulations, suggesting hidden multi-stability within one cell type. Despite clonality, the Sca-1 outliers had distinct transcriptomes. Although their unique gene expression profiles eventually reverted to that of the median cells, revealing an attractor state, they lasted long enough to confer a greatly different proclivity for choosing either the erythroid or the myeloid lineage. Preference in lineage choice was associated with increased expression of lineage-specific transcription factors, such as a >200-fold increase in Gata1 (ref. 10) among the erythroid-prone cells, or a >15-fold increased PU.1 (Sfpi1) (ref. 11) expression among myeloid-prone cells. Thus, clonal heterogeneity of gene expression level is not due to independent noise in the expression of individual genes, but reflects metastable states of a slowly fluctuating transcriptome that is distinct in individual cells and may govern the reversible, stochastic priming of multipotent progenitor cells in cell fate decision.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, Ly / genetics
  • Antigens, Ly / metabolism
  • Cell Differentiation
  • Cell Line
  • Cell Lineage / genetics*
  • Clone Cells / cytology
  • Clone Cells / metabolism
  • Erythroid Cells / cytology
  • Erythroid Cells / metabolism
  • GATA1 Transcription Factor / metabolism
  • Gene Expression Profiling*
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Myeloid Cells / cytology
  • Myeloid Cells / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Stochastic Processes
  • Trans-Activators / metabolism
  • Transcription, Genetic / genetics*

Substances

  • Antigens, Ly
  • GATA1 Transcription Factor
  • Gata1 protein, mouse
  • Ly6a protein, mouse
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • Trans-Activators
  • proto-oncogene protein Spi-1

Associated data

  • GEO/GSE10772