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

Publication Type:

Journal Article

Source:

Nature, Volume 460, Issue 7259, p.1093-7 (2009)

Keywords:

2009, Animals, Basic Sciences Division, beta-Globins, Carrier Proteins, Center-Authored Paper, Clinical Research Division, Comparative Medicine Core Facility, Embryo, Mammalian, Evolution, Molecular, Fetus, gamma-Globins, Gene Expression Regulation, Developmental, Gene Silencing, Globins, Hematopoiesis, Humans, MICE, Nuclear Proteins, Scientific Imaging Core Facility, Shared Resources, Species Specificity

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 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.