Duplicated downstream enhancers control expression of the human apolipoprotein E gene in macrophages and adipose tissue
Open accessAbstract
Two distal enhancers that specify apolipoprotein (apo) E gene expression in isolated macrophages and adipose tissue were identified in transgenic mice that were generated with constructs of the human apoE/C-I/C-I'/C-IV/C-II gene cluster. One of these enhancers, multienhancer 1, consists of a 620-nucleotide sequence located 3.3 kilobases (kb) downstream of the apoE gene. The second enhancer, multienhancer 2, is a 619-nucleotide sequence located 15.9 kb downstream of the apoE gene and 5.9 kb downstream of the apoC-I gene. The two enhancers are 95% identical in sequence, and they are likely to have arisen as a consequence of the gene duplication event that yielded the apoC-I gene and the apoC-I' pseudogene. Both enhancer sequences appear to have equivalent activity in directing apoE gene expression in peritoneal macrophages and in adipocytes, suggesting that their activity in specific cell types may be determined by common regulatory elements.
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APOE expression is induced by complex formation with RXR and several transcription factors, not only on the promoter but also on the enhancer region.
“APOE expression is induced by complex formation with RXR and several transcription factors, not only on the promoter but also on the enhancer region (59, 60)”
From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [59]
The Results and Discussion (page unavailable) show that downstream enhancers are needed for apoE expression in macrophages and identify binding motifs for GR and C/EBP in those enhancers; they also describe a previously reported promoter element that binds AP-1. The paper does not identify RXR as part of an apoE-regulating complex or demonstrate that complex formation at the enhancers induces expression. It says the proposed transcription-factor roles require functional tests. (LLM, conf=0.88)
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Enhancer variants associated with Alzheimer’s disease affect gene expression via chromatin looping
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“This region is known as multienhancer 1 and affects APOE expression in various tissues or cell types, including macrophages, adipose tissue, and a neuronal cell line [41, 42].”
BackgroundNuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes
Komai, M., Noda, Y., Ikeda, A., Kaneshiro, N., Kamikubo, Y., Sakurai, T., Uehara, T., & Takasugi, N. (2024) · Journal of Lipid Research · doi:10.1016/j.jlr.2024.100510 · Cited by 13 · see citing works
- Authors
- Shih, S.-J., Allan, C., Grehan, S., Tse, E., Moran, C., & Taylor, J. M.
- Affiliations
- Gladstone Institutes (US)
- Corresponding author
- Taylor, John M.
- ORCID
- Taylor, John M.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-10
- Volume
- 275
- Issue
- 41
- Pages
- 31567-31572
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2054099490
- Cited by
- 112
- References
- 5
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 9 · 2022: 4 · 2019: 5 · 2018: 4 · 2017: 5 · 2016: 1 · 2015: 3 · 2014: 3 · 2013: 2 · 2012: 4
- FWCI
- 2.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL 37063, R01HL037063)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- apolipoprotein E gene, distal enhancers, gene duplication, macrophages, adipocytes, adipose tissue, peritoneal macrophages, transgenic mice, gene expression regulation, tissue-specific gene expression
- MeSH terms
- Adipose Tissue, Animals, Apolipoproteins C, Apolipoproteins E, Base Sequence, Enhancer Elements, Genetic, Gene Expression Regulation, Multigene Family, Humans, Mice, Transgenic, Molecular Sequence Data, RNA, Messenger, In Situ Hybridization, Sequence Analysis, DNA, Macrophages, Peritoneal, Genes, Duplicate, Mice
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