Inferring rules of lineage commitment in haematopoiesis

Abstract

Population-based studies in the haematopoietic system have suggested that global transcriptional noise drives lineage choice, with transcriptome-wide reversible changes occurring in self-renewing populations. Enver and colleagues use single-cell analysis to show that multipotent cells undergo independent activation of a few individual regulators that can sometimes induce a transition to the committed state. 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 commitment1,2,3,4,5,6. 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 programs7. 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.

Cite this article

Pina, C., Fugazza, C., Tipping, A. et al. Inferring rules of lineage commitment in haematopoiesis. Nat Cell Biol 14, 287–294 (2012). https://doi.org/10.1038/ncb2442

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