Developmental and species-divergent globin switching are driven by BCL11A View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-08

AUTHORS

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

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. More... »

PAGES

1093

Journal

TITLE

Nature

ISSUE

7259

VOLUME

460

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature08243

DOI

http://dx.doi.org/10.1038/nature08243

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1015592887

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/19657335


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