Effects of altered gene order or orientation of the locus control region on human β-globin gene expression in mice
Abstract
The five human beta-type-globin genes, epsilon, Ggamma, Agamma, delta and beta, are close together and are regulated by a locus control region (LCR) located at the 5' end of the locus. Here we investigate the functional consequences of this organization with respect to temporal regulation of the individual genes, by using recombination techniques to invert the order of either the genes or the LCR in vivo. Our analysis of transgenic mice bearing either normal or mutant transgenes leads to two new observations. First, the position of the epsilon-globin gene next to the LCR is mandatory for its expression during the yolk-sac stage of erythropoiesis. Second, LCR activity is orientation dependent, and so the LCR does not act as a simple enhancer to stimulate transcription of the globin genes. Thus, in the absence of any change in transgene integration position, transgene copy number, trans-acting factors or other resident genetic information, simple inversion of the human genes or the LCR fundamentally alters the transcription of beta-type globin genes.
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In globin gene clusters, promoters of various genes compete for contact with upstream enhancers (LCR); promoters located closer to the LCR along the DNA are preferentially activated.
“In globin gene clusters, promoters of various genes compete for contact with upstream enhancers (Locus Control Region, LCR); promoters located closer to the LCR along the DNA are preferentially activated [138].”
From Enhancer Function in the 3D Genome (2023) · cites this paper as [138]
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- Authors
- Tanimoto, K., Liu, Q., Bungert, J., & Engel, J. D.
- Affiliations
- Northwestern University (US)
- Venue
- Nature
- Published
- 1999-03
- Volume
- 398
- Issue
- 6725
- Pages
- 344-348
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1981309824
- Cited by
- 178
- References
- 25
- Citations by year
- 2025: 5 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 7 · 2019: 4 · 2018: 2 · 2017: 3 · 2016: 5 · 2015: 7 · 2014: 5 · 2013: 1 · 2012: 6
- FWCI
- 10.19
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Cooley's Anemia Foundation
- Naito Foundation
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- Robert H. Lurie Comprehensive Cancer Center
- Australian Research Council
- National Health and Medical Research Council
- National Medical Research Council
- Japan Society for the Promotion of Science
- National Heart, Lung, and Blood Institute (R01HL024415)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK052356)
- Topics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- locus control region, beta-globin gene, gene order, gene orientation, epsilon-globin, globin gene expression, temporal regulation, transgenic mice, gene inversion, enhancer activity, transcriptional regulation
- MeSH terms
- Animals, Chromosome Mapping, Erythropoiesis, Female, Gene Expression Regulation, Globins, Humans, Chromosome Inversion, Male, Mice, Transgenic, Recombination, Genetic, Regulatory Sequences, Nucleic Acid, Yolk Sac, Chromosomes, Artificial, Yeast, Gene Expression Regulation, Developmental, Reverse Transcriptase Polymerase Chain Reaction, Mice
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