Adventitious changes in long-range gene expression caused by polymorphic structural variation and promoter competition
Open accessAbstract
It is well established that all of the cis -acting sequences required for fully regulated human α-globin expression are contained within a region of ≈120 kb of conserved synteny. Here, we show that activation of this cluster in erythroid cells dramatically affects expression of apparently unrelated and noncontiguous genes in the 500 kb surrounding this domain, including a gene ( NME4 ) located 300 kb from the α-globin cluster. Changes in NME4 expression are mediated by physical cis -interactions between this gene and the α-globin regulatory elements. Polymorphic structural variation within the globin cluster, altering the number of α-globin genes, affects the pattern of NME4 expression by altering the competition for the shared α-globin regulatory elements. These findings challenge the concept that the genome is organized into discrete, insulated regulatory domains. In addition, this work has important implications for our understanding of genome evolution, the interpretation of genome-wide expression, expression-quantitative trait loci, and copy number variant analyses.
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The human α-globin enhancers may influence the expression of a gene (NME4) lying 400kb away and outside of the orthologous region described here.
“we have previously shown that the human α-globin enhancers may influence the expression of a gene (NME4) lying 400kb away and outside of the orthologous region described here37.”
From Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo (2017) · cites this paper as [37]
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- Authors
- Lower, K. M., Hughes, J. R., De Gobbi, M., Henderson, S., Viprakasit, V., Fisher, C., Goriely, A., Ayyub, H., Sloane-Stanley, J., Vernimmen, D., Langford, C., Garrick, D., Gibbons, R. J., & Higgs, D. R.
- Affiliations
- John Radcliffe Hospital (GB)
- Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, The John Radcliffe Hospital, Headington, Oxford, OX3 9DS, United Kingdom;
- Mahidol University (TH)
- Wellcome Sanger Institute (GB)
- Corresponding author
- Higgs, Douglas R.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-12-22
- Volume
- 106
- Issue
- 51
- Pages
- 21771-21776
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2799829
- OpenAlex
- W2036488627
- Cited by
- 92
- References
- 26
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 6 · 2016: 2 · 2015: 4 · 2014: 10 · 2013: 10 · 2012: 9
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Flinders Academic Commons (Flinders University) (submittedVersion)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- Wellcome Trust
- Hadassah Medical Organization
- NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
- National Institute for Health and Care Research
- King's College London
- University of Oxford
- Universiteit Leiden
- Leids Universitair Medisch Centrum
- Medical Research Council
- 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 › Genetics › Genetic Associations and Epidemiology
- Keywords
- alpha-globin gene cluster, NME4, promoter competition, cis-interactions, copy number variation, long-range gene regulation, erythroid cells, regulatory domain, genome evolution, expression quantitative trait loci
- MeSH terms
- Chromosomes, Human, Pair 16, Humans, Promoter Regions, Genetic, Regulatory Sequences, Nucleic Acid, Gene Expression, Telomere, Polymorphism, Single Nucleotide, alpha-Globins
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