Abstract
Deletions at the 3' end of the human beta-globin locus are associated with the hereditary persistence of fetal hemoglobin (HPFH) in adults, potentially through the juxtaposition of enhancer elements in the vicinity of the fetal gamma-globin genes. We have tested how sequences at the HPFH-2, HPFH-3, and HPFH-6 breakpoints, which act as enhancers in vitro, affect the silencing of a locus control region A gamma (LCRA gamma) transgene in the adult stage of mice. We found persistent A gamma expression in the adult blood of most of the multicopy HPFH-2, HPFH-3, or HPFH-6 lines, in contrast to the control LCRA gamma lines which were silenced. Cre-mediated generation of single copy lines showed persistent gamma gene expression maintained in some of the HPFH-2 and HPFH-6 lines, but not in any of the HPFH-3 or LCRA gamma lines. In the HPFH-2 and HPFH-6 lines, persistent gamma gene expression correlated with euchromatic transgene integrations. Thus, our observations provide support for a model whereby HPFH conditions arise from the juxtaposition of enhancers as well as permissive chromatin subdomains in the vicinity of the gamma-globin genes.
| Original language | English |
|---|---|
| Pages (from-to) | 3412-9 |
| Number of pages | 8 |
| Journal | Blood |
| Volume | 102 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 1 Nov 2003 |
Keywords
- Adult
- Amino Acid Sequence
- Animals
- Enhancer Elements, Genetic
- Fetal Hemoglobin/genetics
- Gene Dosage
- Gene Expression Regulation, Developmental
- Gene Silencing
- Genes, Switch
- Globins/genetics
- Humans
- Locus Control Region/genetics
- Mice
- Mice, Transgenic
- Sequence Deletion/physiology