Epigenetic Regulation of Cell Type–Specific Expression Patterns in the Human Mammary Epithelium
Open accessAbstract
Differentiation is an epigenetic program that involves the gradual loss of pluripotency and acquisition of cell type-specific features. Understanding these processes requires genome-wide analysis of epigenetic and gene expression profiles, which have been challenging in primary tissue samples due to limited numbers of cells available. Here we describe the application of high-throughput sequencing technology for profiling histone and DNA methylation, as well as gene expression patterns of normal human mammary progenitor-enriched and luminal lineage-committed cells. We observed significant differences in histone H3 lysine 27 tri-methylation (H3K27me3) enrichment and DNA methylation of genes expressed in a cell type-specific manner, suggesting their regulation by epigenetic mechanisms and a dynamic interplay between the two processes that together define developmental potential. The technologies we developed and the epigenetically regulated genes we identified will accelerate the characterization of primary cell epigenomes and the dissection of human mammary epithelial lineage-commitment and luminal differentiation.
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During tumorigenic progression, loss of expression of tumor suppressors RB1, BRCA1, APC, MLH1, and VHL has been observed due to hypermethylation at the promoter level.
“To cite an example, during tumorigenic progression, the loss of the expression of tumor suppressors—such as RB1; breast cancer type 1, BRCA1; anaphase promoting complex, APC; DNA mismatch repair protein MLH1; and Von Hippel–Lindau tumor suppressor VHL—has been observed due to hypermethylation at the promoter level.”
From Revisiting Epigenetics Fundamentals and Its Biomedical Implications (2024) · cites this paper as [88]
The Results section on cell type–specific DNA methylation patterns (page unavailable) reports that methylation near promoters is associated with lower gene expression in mammary epithelial cells. It does not report promoter hypermethylation causing loss of RB1, BRCA1, APC, MLH1, or VHL expression during tumorigenic progression. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn cancer, epigenetic dysregulation involves ncRNAs, particularly miRNAs and lncRNAs, as well as alterations in methylation and acetylation.
“In cancer, epigenetic dysregulation involves ncRNAs, in particular miRNAs, and lncRNAs, which comprise the most studied RNAs, as well as alterations in methylation and acetylation [88].”
From Revisiting Epigenetics Fundamentals and Its Biomedical Implications (2024) · cites this paper as [88]
The Introduction (page unavailable) says that DNA methylation, histone modification, and non-coding RNAs play roles in tumorigenesis. It does not identify miRNAs or lncRNAs, say they are the most studied RNAs, or specify acetylation; the Results passages instead discuss histone methylation. (LLM, conf=0.85)
Experimental — accuracy not yet measuredmiRNAs target the BACE1 protein that regulates the production of amyloid beta platelets, Aβ, which when accumulated contribute to neuroinflammation and progression of Alzheimer's disease.
“Likewise, it has been reported that there are miRNAs that target the BACE1 protein that regulates the production of amyloid beta platelets, Aβ, which, when accumulated, contribute to the neuroinflammation and progression of this disease [86,87,88].”
From Revisiting Epigenetics Fundamentals and Its Biomedical Implications (2024) · cites this paper as [88]
The Results passage on gene expression and histone modification patterns and the Discussion passage on K27-regulated transcription factors concern human mammary epithelial cells. Searches for BACE1, miRNAs, amyloid beta, neuroinflammation, and Alzheimer’s disease found no passage in our copy addressing the attributed claim. (LLM, conf=0.78)
Experimental — accuracy not yet measuredIn Alzheimer's disease, changes have been identified in the methylation status of CLU, ABCA7, MS4A6A, and CD2AP, which have been reported to contribute to the development of the disease.
“On the other hand, in Alzheimer’s disease, for example, changes have been identified in the methylation status of proteins such as human clusterin CLU; ATP binding cassette subfamily A member 7 ABCA7; MS4A6A; and CD2AP, which have been reported to contribute to the development of the disease.”
From Revisiting Epigenetics Fundamentals and Its Biomedical Implications (2024) · cites this paper as [88]
The Results section on cell type–specific DNA methylation examines CD24+ and CD44+ human mammary epithelial cells, not Alzheimer’s disease. Searches for Alzheimer’s disease and the named genes (CLU, ABCA7, MS4A6A, and CD2AP) found no passage in our copy addressing their methylation or contribution to the disease. No page numbers were available in the indexed passages. (LLM, conf=0.76)
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References 40 · Cited by 108
Research works printed but not linked: 36
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- Authors
- Maruyama, R., Choudhury, S., Kowalczyk, A., Bessarabova, M., Beresford-Smith, B., Conway, T., Kaspi, A., Wu, Z., Nikolskaya, T., Merino, V. F., Lo, P.-K., Liu, X. S., Nikolsky, Y., Sukumar, S., Haviv, I., & Polyak, K.
- Affiliations
- Brigham and Women's Hospital (US)
- The University of Melbourne (AU)
- Thomson Reuters (United States) (US)
- Baker Heart and Diabetes Institute (AU)
- Harvard University (US)
- Johns Hopkins University (US)
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-04-21
- Volume
- 7
- Issue
- 4
- Pages
- e1001369
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC3080862
- OpenAlex
- W2011155783
- Cited by
- 108
- References
- 40
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 6 · 2023: 4 · 2022: 11 · 2021: 8 · 2020: 6 · 2019: 4 · 2018: 7 · 2017: 6 · 2016: 13 · 2015: 11 · 2014: 8 · 2013: 11 · 2012: 8
- FWCI
- 3.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Susan G. Komen for the Cure
- Breast Cancer Research Foundation
- Brigham and Women's Hospital
- Johns Hopkins University
- Canada's Michael Smith Genome Sciences Centre
- Terri Brodeur Breast Cancer Foundation
- BC Cancer Agency
- National Cancer Institute (CA 89393, P50 CA 89393, CA080111, P01CA080111, P50CA089393)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- epigenetic regulation, mammary epithelium, mammary progenitor cells, luminal differentiation, H3K27me3, DNA methylation, histone methylation, cell type-specific gene expression, lineage commitment, developmental potential
- MeSH terms
- Cell Differentiation, Chromatin, Gene Expression Regulation, Histones, Humans, Transcription Factors, Hyaluronan Receptors, DNA Methylation, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Mammary Glands, Human, Epigenesis, Genetic, CD24 Antigen
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