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.
Sankaran
Vijay G
VG
Division of Hematology/Oncology, Children's Hospital Boston and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Xu
Jian
J
Ragoczy
Tobias
T
Ippolito
Gregory C
GC
Walkley
Carl R
CR
Maika
Shanna D
SD
Fujiwara
Yuko
Y
Ito
Masafumi
M
Groudine
Mark
M
Bender
M A
MA
Tucker
Philip W
PW
Orkin
Stuart H
SH
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian / Q000378:metabolism; D019143:Evolution, Molecular; D005333:Fetus / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D005914:Globins / Q000235:genetics*; D006410:Hematopoiesis; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins; D013045:Species Specificity; D055544:beta-Globins / Q000235:genetics; D055545:gamma-Globins / Q000235:genetics
C486563:BCL11A protein, human; C407733:Bcl11a protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D055544:beta-Globins; D055545:gamma-Globins; D005914:Globins