Hierarchical Differentiation of Myeloid Progenitors Is Encoded in the Transcription Factor Network

Jan Krumsiek,Fabian J Theis,Carsten Marr,Timm Schroeder,Maurizio Pesce

doi:10.1371/journal.pone.0022649

Abstract

Hematopoiesis is an ideal model system for stem cell biology with advanced experimental access. A systems view on the interactions of core transcription factors is important for understanding differentiation mechanisms and dynamics. In this manuscript, we construct a Boolean network to model myeloid differentiation, specifically from common myeloid progenitors to megakaryocytes, erythrocytes, granulocytes and monocytes. By interpreting the hematopoietic literature and translating experimental evidence into Boolean rules, we implement binary dynamics on the resulting 11-factor regulatory network. Our network contains interesting functional modules and a concatenation of mutual antagonistic pairs. The state space of our model is a hierarchical, acyclic graph, typifying the principles of myeloid differentiation. We observe excellent agreement between the steady states of our model and microarray expression profiles of two different studies. Moreover, perturbations of the network topology correctly reproduce reported knockout phenotypes in silico. We predict previously uncharacterized regulatory interactions and alterations of the differentiation process, and line out reprogramming strategies.

Highlights

Hematopoiesis – a system with a well-known biological background and advanced experimental access – is considered as a paradigm for stem cell biology [1]
Model construction The scope of our model is the differentiation of common myeloid progenitors (CMPs) into erythrocytes, megakaryocytes, granulocytes and monocytes
We examplarily discuss five such cases. (i) NF-E2 is regulated by GATA-1 and SCL, but important for megakaryocytic development [23,24,25]. (ii) IRF8 is required for macrophage [26] and B-cell [27] differentiation and was excluded. (iii) While C/EBPb is known to rescue targeted disruption of C/EBPa, its primary physiological role lies in macrophage differentiation [28]. (iv) The erythroid transcription factor Gfi-1b is induced by GATA-1 [29] and required in both erythrogenesis and megakaryogenesis [30], and is not involved in the megakaryocyte vs. erythrocyte lineage decision. (v) RUNX1 is an early transcription factor required in hematopoietic stem cell (HSC) [31] which is reused later in the differentiation process for the megakaryocyte lineage [32]

Summary

Introduction

Hematopoiesis – a system with a well-known biological background and advanced experimental access – is considered as a paradigm for stem cell biology [1]. From a single cell type, the hematopoietic stem cell (HSC), all mature blood cells emerge through a hierarchical series of lineage decisions via different progenitor cells [2]. Hematopoiesis is often depicted as a hierarchical differentiation tree, with a HSC at the root and the mature blood cells as the leaves (Figure 1A). One of the intermediate cellular states is the common myeloid progenitor (CMP) [3]. CMPs can proliferate and differentiate into megakaryocyte-erythrocyte (MegE) progenitors and granulocyte-monocyte (GM) progenitors, which further give rise to megakaryocytes, erythrocytes, granulocytes, monocytes and others. In the past 20 years, a number of regulatory interactions between important transcription factors, governing the differentiation process, have been experimentally unraveled (for a review, see [4])

Methods

Results

Conclusion