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Globin gene switching in transgenic mice carrying HS2-globin gene constructs
N A Roberts1, J A Sloane-Stanley, J A Sharpe
1MRC Molecular Haematology Unit, University of Oxford, John Radcliffe Hospital, United Kingdom.
Blood
|January 15, 1997
Summary
Transgenic mice reveal complex interactions in human globin gene switching. Different constructs show varied developmental regulation, with some exhibiting incomplete gamma gene silencing in adults.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Human globin gene switching is a complex developmental process.
- Understanding the regulatory elements controlling this switch is crucial for insights into hemoglobinopathies.
Purpose of the Study:
- To investigate the role of various regulatory elements in human gamma and beta globin gene switching using transgenic mouse models.
- To compare the developmental regulation patterns of different globin gene constructs.
Main Methods:
- Generation and analysis of transgenic mice harboring distinct human gamma and beta globin gene constructs.
- Comparison of gene switching patterns across multiple transgenic lines with varying genetic elements.
- Quantification of gamma messenger RNA (mRNA) levels at different developmental stages.
Main Results:
- Identified three distinct patterns of globin gene switching: rapid, intermediate, and delayed.
- Observed incomplete gamma gene expression in adult mice for certain constructs, particularly those with only HS2.
- Demonstrated that the A gamma enhancer did not alter switching patterns but influenced copy number-dependent expression and caused intrauterine lethality at high levels.
Conclusions:
- Multiple elements within the beta globin gene cluster interact to ensure precise developmental regulation of globin gene expression.
- Gamma gene silencing in adult life is not entirely autonomous and can be incomplete, especially when HS2 is the sole locus control region element.