Inferring rules of lineage commitment in haematopoiesis

Research output: Contribution to journalArticle

Abstract

How the molecular programs of differentiated cells develop as cells transit from multipotency through lineage commitment remains unexplored. This reflects the inability to access cells undergoing commitment or located in the immediate vicinity of commitment boundaries. It remains unclear whether commitment constitutes a gradual process, or else represents a discrete transition. Analyses of in vitro self-renewing multipotent systems have revealed cellular heterogeneity with individual cells transiently exhibiting distinct biases for lineage commitment(1-6). Such systems can be used to molecularly interrogate early stages of lineage affiliation and infer rules of lineage commitment. In haematopoiesis, population-based studies have indicated that lineage choice is governed by global transcriptional noise, with self-renewing multipotent cells reversibly activating transcriptome-wide lineage-affiliated programs(7). We examine this hypothesis through functional and molecular analysis of individual blood cells captured from self-renewal cultures, during cytokine-driven differentiation and from primary stem and progenitor bone marrow compartments. We show dissociation between self-renewal potential and transcriptome-wide activation of lineage programs, and instead suggest that multipotent cells experience independent activation of individual regulators resulting in a low probability of transition to the committed state.

Details

Authors
  • Cristina Pina
  • Cristina Fugazza
  • Alex J. Tipping
  • John Brown
  • Shamit Soneji
  • José Teles
  • Carsten Peterson
  • Tariq Enver
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biophysics
Original languageEnglish
Pages (from-to)287
JournalNature Cell Biology
Volume14
Issue number3
Publication statusPublished - 2012
Publication categoryResearch
Peer-reviewedYes