Locus control regions of mammalian β-globin gene clusters: combining phylogenetic analyses and experimental results to gain functional insights
Abstract
Locus control regions (LCRs) are cis-acting DNA segments needed for activation of an entire locus or gene cluster. They are operationally defined as DNA sequences needed to achieve a high level of gene expression regardless of the position of integration in transgenic mice or stably transfected cells. This review brings together the large amount of DNA sequence data from the beta-globin LCR with the vast amount of functional data obtained through the use of biochemical, cellular and transgenic experimental systems. Alignment of orthologous LCR sequences from five mammalian species locates numerous conserved regions, including previously identified cis-acting elements within the cores of nuclease hypersensitive sites (HSs) as well as conserved regions located between the HS cores. The distribution of these conserved sequences, combined with the effects of LCR fragments utilized in expression studies, shows that important sites are more widely distributed in the LCR than previously anticipated, especially in and around HS2 and HS3. We propose that the HS cores plus HS flanking DNAs comprise a 'unit' to which proteins bind and form an optimally functional structure. Multiple HS units (at least three: HS2, HS3 and HS4 cores plus flanking DNAs) together establish a chromatin structure that allows the proper developmental regulation of genes within the cluster.
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The predominant TF binding sites in HS1 are just two GATA binding elements.
“and the predominant TF binding sites in HS1 are just two GATA binding elements.47”
From Super-enhancers include classical enhancers and facilitators to fully activate gene expression (2023) · cites this paper as [47]
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- Authors
- Hardison, R., Slightom, J. L., Gumucio, D. L., Goodman, M., Stojanovic, N., & Miller, W.
- Affiliations
- Pennsylvania State University (US)
- University of Michigan (US)
- Wayne State University (US)
- Corresponding author
- Hardison, Ross
- Venue
- Gene
- Publisher
- Elsevier BV
- Published
- 1997-12
- Volume
- 205
- Issue
- 1-2
- Pages
- 73-94
- ISSN
- 0378-1119 (ISSN-L)
- OpenAlex
- W2094596493
- Cited by
- 230
- References
- 4
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 2 · 2018: 2 · 2017: 4 · 2016: 3 · 2015: 2 · 2014: 2 · 2013: 2 · 2012: 6
- FWCI
- 1.06
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Gene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK027635, DK27635)
- U.S. National Library of Medicine (R01LM005110, LM05573, LM05110)
- 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 gene cluster, nuclease hypersensitive sites, cis-regulatory elements, HS2, HS3, chromatin structure, developmental gene regulation, transgenic mice, mammalian evolution
- MeSH terms
- Animals, Base Sequence, Multigene Family, Globins, Humans, Molecular Sequence Data, Phylogeny, Species Specificity, Sequence Homology, Amino Acid, Locus Control Region
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