Developmental and species-divergent globin switching are driven by BCL11A

Vijay G. Sankaran, Jian Xu, Tobias Ragoczy, Gregory C. Ippolito, Carl R. Walkley, Shanna D. Maika, Yuko Fujiwara, Masafumi Ito, Mark Groudine, M. A. Bender, Philip W. Tucker and Stuart H. Orkin ()
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Vijay G. Sankaran: Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
Jian Xu: Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
Tobias Ragoczy: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
Gregory C. Ippolito: Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA
Carl R. Walkley: Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
Shanna D. Maika: Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA
Yuko Fujiwara: Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
Masafumi Ito: Japanese Red Cross, Nagoya First Hospital
Mark Groudine: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
M. A. Bender: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
Philip W. Tucker: Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA
Stuart H. Orkin: Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

Nature, 2009, vol. 460, issue 7259, 1093-1097

Abstract: Abstract The contribution of changes in cis-regulatory elements or trans-acting factors to interspecies differences in gene expression is not well understood. The mammalian β-globin loci have served as a model for gene regulation during development. Transgenic mice containing the human β-globin locus, consisting of the linked embryonic (ε), fetal (γ) and adult (β) genes, have been used as a system to investigate the temporal switch from fetal to adult haemoglobin, as occurs in humans. Here we show that the human γ-globin (HBG) genes in these mice behave as murine embryonic globin genes, revealing a limitation of the model and demonstrating that critical differences in the trans-acting milieu have arisen during mammalian evolution. We show that the expression of BCL11A, a repressor of human γ-globin expression identified by genome-wide association studies, differs between mouse and human. Developmental silencing of the mouse embryonic globin and human γ-globin genes fails to occur in mice in the absence of BCL11A. Thus, BCL11A is a critical mediator of species-divergent globin switching. By comparing the ontogeny of β-globin gene regulation in mice and humans, we have shown that alterations in the expression of a trans-acting factor constitute a critical driver of gene expression changes during evolution.

Date: 2009
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DOI: 10.1038/nature08243

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