The Locus Control Region Is Necessary for Gene Expression in the Human β-Globin Locus but Not the Maintenance of an Open Chromatin Structure in Erythroid Cells
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Studies in many systems have led to the model that the human beta-globin locus control region (LCR) regulates the transcription, chromatin structure, and replication properties of the beta-globin locus. However the precise mechanisms of this regulation are unknown. We have developed strategies to use homologous recombination in a tissue culture system to examine how the LCR regulates the locus in its natural chromosomal environment. Our results show that when the functional components of the LCR, as defined by transfection and transgenic studies, are deleted from the endogenous beta-globin locus in an erythroid background, transcription of all beta-globin genes is abolished in every cell. However, formation of the remaining hypersensitive site(s) of the LCR and the presence of a DNase I-sensitive structure of the beta-globin locus are not affected by the deletion. In contrast, deletion of 5'HS5 of the LCR, which has been suggested to serve as an insulator, has only a minor effect on beta-globin transcription and does not influence the chromatin structure of the locus. These results show that the LCR as currently defined is not necessary to keep the locus in an "open" conformation in erythroid cells and that even in an erythroid environment an open locus is not sufficient to permit transcription of the beta-like globin genes.
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The mammalian β-globin locus developmental β-globin genes are regulated by a powerful tissue-specific enhancer known as a locus control region (LCR).
“These models were initially applied to the mammalian β-globin locus, in which the developmental β-globin genes are regulated by a powerful tissue-specific enhancer known as a locus control region (LCR) [254–257].”
From Transcriptional enhancers and their communication with gene promoters (2021) · cites this paper as [255]
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- Authors
- Reik, A., Telling, A., Zitnik, G., Cimbora, D., Epner, E., & Groudine, M.
- Affiliations
- Fred Hutch Cancer Center (US)
- University of Washington (US)
- Corresponding author
- Groudine, Mark
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 1998-10
- Volume
- 18
- Issue
- 10
- Pages
- 5992-6000
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC109185
- OpenAlex
- W2127397885
- Cited by
- 163
- References
- 5
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 1 · 2021: 7 · 2020: 2 · 2019: 1 · 2018: 1 · 2016: 1 · 2014: 2 · 2013: 3
- FWCI
- 6.06
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Cancer Society
- Leukemia Research Foundation
- Deutsche Forschungsgemeinschaft
- National Institutes of Health (5r01ca054337-10)
- National Cancer Institute (CA54337)
- National Institute of Diabetes and Digestive and Kidney Diseases (R37DK044746, DK52854, DK 44746)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Keywords
- locus control region, beta-globin locus, erythroid cells, chromatin structure, open chromatin, hypersensitive sites, insulators, homologous recombination
- MeSH terms
- Adult, Animals, Cell Line, Chickens, Chromatin, Gene Expression Regulation, Globins, Humans, Erythroid Precursor Cells, Locus Control Region
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