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Published on: August 13, 2010
Developmental and species-divergent globin switching are driven by BCL11A
Vijay G Sankaran1, Jian Xu, Tobias Ragoczy
1Division 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.
Nature
|August 7, 2009
Summary
Trans-acting factors, like BCL11A, drive species-specific gene expression changes during evolution. Differences in BCL11A expression explain why human fetal hemoglobin genes function as embryonic genes in mice.
Area of Science:
- Developmental Biology
- Evolutionary Genetics
- Molecular Biology
Background:
- Understanding interspecies gene expression differences requires studying cis-regulatory elements and trans-acting factors.
- Mammalian beta-globin loci are key models for developmental gene regulation.
- Transgenic mice with human beta-globin loci model human fetal to adult hemoglobin switching.
Purpose of the Study:
- Investigate the role of trans-acting factors in species-divergent gene regulation.
- Determine the limitations of mouse models for human globin switching.
- Identify key factors mediating evolutionary changes in gene expression.
Main Methods:
- Utilized transgenic mice carrying the human beta-globin locus.
- Compared gene expression patterns between human and mouse systems.
- Analyzed the role of BCL11A as a repressor of gamma-globin expression.
Main Results:
- Human gamma-globin (HBG) genes in mice mimicked murine embryonic globin gene behavior.
- BCL11A expression differs significantly between mice and humans.
- Absence of BCL11A prevented developmental silencing of both mouse embryonic and human gamma-globin genes.
Conclusions:
- BCL11A is a critical mediator of species-divergent globin switching.
- Altered trans-acting factor expression is a major driver of evolutionary gene expression changes.
- Mouse models have limitations in fully recapitulating human developmental gene regulation.
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