Developmental and species-divergent globin switching are driven by BCL11A

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. The embryo-to-fetus transition in vertebrates is marked by a developmental switch between genes encoding γ-globin in the blood, and there are differences in how globin gene expression is developmentally regulated in mouse versus humans. An experiment involving the insertion of the human β-globin locus, together with 100 kilobases of the surrounding DNA, into the mouse genome, shows that the BCL11A gene is responsible for this difference in regulation. BCLA11A protein is a repressor of human γ-globin expression previously identified by genome-wide association studies. This example of an alteration in gene expression that has occurred during evolution also provides possible new clues as to the mechanism of the clinically important fetal-to-adult haemoglobin switch in humans. The contribution of changes in cis-regulatory elements or trans-acting factors to differences in gene expression between species is not well understood. Here it is found that, in transgenic mice containing the human β-globin locus, the expression of BCL11A differs between mouse and human and is a critical mediator of species-divergent globin switching.