Single-molecule imaging of transcription dynamics in somatic stem cells

Nature. 2020 Jul;583(7816):431-436. doi: 10.1038/s41586-020-2432-4. Epub 2020 Jun 24.

Abstract

Molecular noise is a natural phenomenon that is inherent to all biological systems1,2. How stochastic processes give rise to the robust outcomes that support tissue homeostasis remains unclear. Here we use single-molecule RNA fluorescent in situ hybridization (smFISH) on mouse stem cells derived from haematopoietic tissue to measure the transcription dynamics of three key genes that encode transcription factors: PU.1 (also known as Spi1), Gata1 and Gata2. We find that infrequent, stochastic bursts of transcription result in the co-expression of these antagonistic transcription factors in the majority of haematopoietic stem and progenitor cells. Moreover, by pairing smFISH with time-lapse microscopy and the analysis of pedigrees, we find that although individual stem-cell clones produce descendants that are in transcriptionally related states-akin to a transcriptional priming phenomenon-the underlying transition dynamics between states are best captured by stochastic and reversible models. As such, a stochastic process can produce cellular behaviours that may be incorrectly inferred to have arisen from deterministic dynamics. We propose a model whereby the intrinsic stochasticity of gene expression facilitates, rather than impedes, the concomitant maintenance of transcriptional plasticity and stem cell robustness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult Stem Cells / cytology
  • Adult Stem Cells / metabolism*
  • Animals
  • Cells, Cultured
  • Clone Cells / cytology
  • Clone Cells / metabolism
  • Female
  • GATA1 Transcription Factor / genetics
  • GATA2 Transcription Factor / genetics
  • Gene Expression Regulation*
  • Gene Regulatory Networks
  • In Situ Hybridization, Fluorescence
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pedigree
  • Proto-Oncogene Proteins / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Single Molecule Imaging*
  • Stochastic Processes
  • Trans-Activators / genetics
  • Transcription, Genetic / genetics*

Substances

  • GATA1 Transcription Factor
  • GATA2 Transcription Factor
  • Gata1 protein, mouse
  • Gata2 protein, mouse
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Trans-Activators
  • proto-oncogene protein Spi-1