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Molecular and Cellular Biology, January 2004, p. 741-756, Vol. 24, No. 2
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.2.741-756.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Molecular Signatures of Self-Renewal, Differentiation, and Lineage Choice in Multipotential Hemopoietic Progenitor Cells In Vitro

Ludovica Bruno,1,2,{dagger} Reinhard Hoffmann,2,{dagger},{ddagger} Fraser McBlane,2,§ John Brown,1 Rajeev Gupta,1 Chirag Joshi,1 Stella Pearson,3 Thomas Seidl,1,2 Clare Heyworth,3 and Tariq Enver1*

Section of Gene Function and Regulation, The Institute of Cancer Research, London SW3 6JB,1 Cancer Research UK Experimental Haematology Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester M20 4BX, United Kingdom,3 Basel Institute for Immunology, 4005 Basel, Switzerland2

Received 12 May 2003/ Returned for modification 25 June 2003/ Accepted 2 October 2003

The molecular mechanisms governing self-renewal, differentiation, and lineage specification remain unknown. Transcriptional profiling is likely to provide insight into these processes but, as yet, has been confined to "static" molecular profiles of stem and progenitors cells. We now provide a comprehensive, statistically robust, and "dynamic" analysis of multipotent hemopoietic progenitor cells undergoing self-renewal in response to interleukin-3 (IL-3) and multilineage differentiation in response to lineage-affiliated cytokines. Cells undergoing IL-3-dependent proliferative self-renewal displayed striking complexity, including expression of genes associated with different lineage programs, suggesting a highly responsive compartment poised to rapidly execute intrinsically or extrinsically initiated cell fate decisions. A remarkable general feature of early differentiation was a resolution of complexity through the downregulation of gene expression. Although effector genes characteristic of mature cells were upregulated late, coincident with morphological changes, lineage-specific changes in gene expression were observed prior to this, identifying genes which may provide early harbingers of unilineage commitment. Of particular interest were genes that displayed differential behavior irrespective of the lineage elaborated, many of which were rapidly downregulated within 4 to 8 h after exposure to a differentiation cue. These are likely to include genes important in self-renewal, the maintenance of multipotentiality, or the negative regulation of differentiation per se.

* Corresponding author. Mailing address: MRC Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX3 9DS. Phone: 44-1865-222-421. Fax: 44-1865-222-449. E-mail: tenver{at}gwmail.jr2.ox.ac.uk.

{dagger} L.B. and R.H. contributed equally to this study.

{ddagger} Present address: Department of Bacteriology, Max-von-Pettenkofer-Institut, 80336 Munich, Germany.

§ Present address: Department Experimental Oncology, European Institute of Oncology, Milan 20141, Italy.

Molecular and Cellular Biology, January 2004, p. 741-756, Vol. 24, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.2.741-756.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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