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Developmental and species-divergent globin switching are driven by BCL11A.

The contribution of changes in cis-regulatory elements or trans-acting factors to interspecies differences in gene expression is not well understood. The mammalian beta-globin loci have served as a model for gene regulation during development. Transgenic mice containing the human beta-globin locus, consisting of the linked embryonic (epsilon), fetal (gamma) and adult (beta) 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 gamma-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 gamma-globin expression identified by genome-wide association studies, differs between mouse and human. Developmental silencing of the mouse embryonic globin and human gamma-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 beta-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.

Pubmed ID: 19657335

Authors

  • Sankaran VG
  • Xu J
  • Ragoczy T
  • Ippolito GC
  • Walkley CR
  • Maika SD
  • Fujiwara Y
  • Ito M
  • Groudine M
  • Bender MA
  • Tucker PW
  • Orkin SH

Journal

Nature

Publication Data

August 27, 2009

Associated Grants

  • Agency: NHLBI NIH HHS, Id: P01 HL032262
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Carrier Proteins
  • Embryo, Mammalian
  • Evolution, Molecular
  • Fetus
  • Gene Expression Regulation, Developmental
  • Gene Silencing
  • Globins
  • Hematopoiesis
  • Humans
  • Mice
  • Nuclear Proteins
  • Species Specificity
  • beta-Globins
  • gamma-Globins