Computational Modeling of the Hematopoietic Erythroid-Myeloid Switch Reveals Insights into Cooperativity, Priming, and Irreversibility

• DOI: 10.1371/journal.pcbi.1000268
• Publication Date: 2009-01-22T22:58:03Z
• Authors: Vijay Chickarmane; Tariq Enver; Carsten Peterson
• Keywords: Bistability; Lineage (genetic); Cooperativity; Gene regulatory network; Priming (agriculture)

Hematopoietic stem cell lineage choices are decided by genetic networks that turned ON/OFF in a switch-like manner. However, prior to commitment, genes primed at low expression levels. Understanding the underlying molecular circuitry terms of how it governs both state and, other extreme, committed is relevance not only hematopoiesis but also developmental systems general. We develop computational model for hematopoietic erythroid-myeloid decision, which determined switch involving PU.1 and GATA-1. Dynamical models based upon known interactions between these master genes, such as mutual antagonism autoregulation, fail make system bistable, desired feature robust determination. therefore suggest new mechanism cofactor regulated well recruited one bind antagonistic partner necessary bistability hence behavior. An interesting fallout from this architecture suppression through external means can lead loss cooperativity, The PU.1-GATA-1 interacts with another mutually pair, C/EBPalpha-FOG-1. latter pair inherits its upstream further reinforces decision due several feedback loops, thereby leading irreversible commitment. switch, handles an example network implements regulating cooperativity recruitment cofactors. Perturbing regulators downstream targets suggests potential reprogramming strategies. approach points framework commitment studies general could aid search lineage-determining genes.