Developmental and species-divergent globin switching are driven by BCL11A

作者：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^*

来源：Nature, 2009, 460(7259): 1093-U50.

DOI：10.1038/nature08243

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.

• 出版日期2009-8-27