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Developmental and species-divergent globin switching are driven by BCL11A

Nature volume 460, pages 1093–1097 (2009)Cite this article

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.

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Figure 1: Human γ-globin is primarily expressed in primitive erythroid cells of β-locus mice.
Figure 2: PT-FISH analysis shows that γ-globin expression parallels the murine embryonic globins in primitive erythroid cells.
Figure 3: BCL11A expression varies between humans and mice, suggesting a model for trans -acting variation in β-globin gene expression.
Figure 4: Bcl11a -/- mice fail to silence the expression of mouse embryonic β-like globins and human γ-globin genes.

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Acknowledgements

We are grateful to K. Peterson and H. Fedosyuk for providing β-locus mice, K. Gaensler for the A20 and A85 strains of β-locus mice, and T. Jacks for providing the K-RasG12D mice. We thank J. Palis and P. Kingsley for providing mouse embryonic globin antibodies, H. Mikkola and B. Van Handel for providing sorted human samples, and R. Byron and A. Telling for technical support. We thank L. Zon, K. McGrath, P. Kingsley, J. Palis, M. Kowalczyk and T. Menne for advice and discussions. This work was supported by funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) (S.H.O. and M.G.) and the National Cancer Institute (P.W.T.). S.H.O. is an Investigator of the Howard Hughes Medical Institute (HHMI). C.R.W. is a special fellow of the Leukemia & Lymphoma Society. T.R. is supported by a fellowship from the American Society of Hematology. J.X. is an HHMI fellow of the Helen Hay Whitney Foundation. V.G.S. is supported by a Medical Scientist Training Program Award from the NIH and G.C.I. is supported by a NCI postdoctoral fellowship.

Author Contributions V.G.S., J.X. and S.H.O. conceived the study design. V.G.S., J.X., T.R., C.R.W., Y.F., M.I. and M.A.B. performed the experiments. V.G.S., J.X., T.R., C.R.W., M.G., M.A.B. and S.H.O. analysed data. G.C.I., S.D.M. and P.W.T. developed and contributed a new mouse line. V.G.S., J.X. and S.H.O. wrote the paper. All authors read, helped revise, and approved the manuscript.

Author information

Author notes

  1. Carl R. Walkley

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

  2. Vijay G. Sankaran and Jian Xu: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology/Oncology, Children’s Hospital Boston and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Vijay G. Sankaran, Jian Xu, Carl R. Walkley, Yuko Fujiwara & Stuart H. Orkin

  2. Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA ,

    Jian Xu, Yuko Fujiwara & Stuart H. Orkin

  3. Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA ,

    Tobias Ragoczy, Mark Groudine & M. A. Bender

  4. Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712, USA ,

    Gregory C. Ippolito, Shanna D. Maika & Philip W. Tucker

  5. Department of Pathology, Japanese Red Cross, Nagoya First Hospital, Nagoya, Japan

    Masafumi Ito

  6. Department of Radiation Oncology, and,

    Mark Groudine

  7. Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA,

    M. A. Bender

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  1. Vijay G. Sankaran
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Correspondence to Stuart H. Orkin.

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Competing interests

V.G.S. and S.H.O. are inventors on a patent filed by the Children’s Hospital of Boston related to the therapeutic targeting of BCL11A for induction of fetal haemoglobin in humans.

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Sankaran, V., Xu, J., Ragoczy, T. et al. Developmental and species-divergent globin switching are driven by BCL11A. Nature 460, 1093–1097 (2009). https://doi.org/10.1038/nature08243

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