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Developmental and species-divergent globin switching are driven by BCL11A

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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
    Howard Hughes Medical Institute, 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
    Present address: St Vincent’s Institute of Medical Research, Fitzroy, Victoria 3065, Australia.)

  • 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
    Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA)

  • Masafumi Ito

    (Japanese Red Cross, Nagoya First Hospital)

  • Mark Groudine

    (Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
    and)

  • M. A. Bender

    (Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
    University of Washington, Seattle, Washington 98195, 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
    Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA)

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.

Suggested Citation

  • 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 & Stuart H. Orki, 2009. "Developmental and species-divergent globin switching are driven by BCL11A," Nature, Nature, vol. 460(7259), pages 1093-1097, August.
    • Handle: RePEc:nat:nature:v:460:y:2009:i:7259:d:10.1038_nature08243
    DOI: 10.1038/nature08243
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    Cited by:

    1. Jacob C Ulirsch & Jessica N Lacy & Xiuli An & Narla Mohandas & Tarjei S Mikkelsen & Vijay G Sankaran, 2014. "Altered Chromatin Occupancy of Master Regulators Underlies Evolutionary Divergence in the Transcriptional Landscape of Erythroid Differentiation," PLOS Genetics, Public Library of Science, vol. 10(12), pages 1-19, December.

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