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, Stuart H. Orkin

Research output: Contribution to journalArticle

242 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1093-1097
Number of pages5
JournalNature
Volume460
Issue number7259
DOIs
StatePublished - Aug 27 2009

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Globins
Genes
Trans-Activators
Gene Expression
Genome-Wide Association Study
Transgenic Mice
Hemoglobins

ASJC Scopus subject areas

  • General

Cite this

Sankaran, V. G., Xu, J., Ragoczy, T., Ippolito, G. C., Walkley, C. R., Maika, S. D., ... Orkin, S. H. (2009). Developmental and species-divergent globin switching are driven by BCL11A. Nature, 460(7259), 1093-1097. https://doi.org/10.1038/nature08243

Developmental and species-divergent globin switching are driven by BCL11A. / Sankaran, Vijay G.; Xu, Jian; Ragoczy, Tobias; Ippolito, Gregory C.; Walkley, Carl R.; Maika, Shanna D.; Fujiwara, Yuko; Ito, Masafumi; Groudine, Mark; Bender, M. A.; Tucker, Philip W.; Orkin, Stuart H.

In: Nature, Vol. 460, No. 7259, 27.08.2009, p. 1093-1097.

Research output: Contribution to journalArticle

Sankaran, VG, Xu, J, Ragoczy, T, Ippolito, GC, Walkley, CR, Maika, SD, Fujiwara, Y, Ito, M, Groudine, M, Bender, MA, Tucker, PW & Orkin, SH 2009, 'Developmental and species-divergent globin switching are driven by BCL11A', Nature, vol. 460, no. 7259, pp. 1093-1097. https://doi.org/10.1038/nature08243
Sankaran VG, Xu J, Ragoczy T, Ippolito GC, Walkley CR, Maika SD et al. Developmental and species-divergent globin switching are driven by BCL11A. Nature. 2009 Aug 27;460(7259):1093-1097. https://doi.org/10.1038/nature08243
Sankaran, Vijay G. ; Xu, Jian ; Ragoczy, Tobias ; Ippolito, Gregory C. ; Walkley, Carl R. ; Maika, Shanna D. ; Fujiwara, Yuko ; Ito, Masafumi ; Groudine, Mark ; Bender, M. A. ; Tucker, Philip W. ; Orkin, Stuart H. / Developmental and species-divergent globin switching are driven by BCL11A. In: Nature. 2009 ; Vol. 460, No. 7259. pp. 1093-1097.
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