The selection and function of cell type-specific enhancers
Open accessAbstract
The human body contains several hundred cell types, all of which share the same genome. In metazoans, much of the regulatory code that drives cell type-specific gene expression is located in distal elements called enhancers. Although mammalian genomes contain millions of potential enhancers, only a small subset of them is active in a given cell type. Cell type-specific enhancer selection involves the binding of lineage-determining transcription factors that prime enhancers. Signal-dependent transcription factors bind to primed enhancers, which enables these broadly expressed factors to regulate gene expression in a cell type-specific manner. The expression of genes that specify cell type identity and function is associated with densely spaced clusters of active enhancers known as super-enhancers. The functions of enhancers and super-enhancers are influenced by, and affect, higher-order genomic organization.
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H3K27ac is enriched in accessible regions, consistent with its known association with active promoters and enhancers.
“Based on ChIP-seq and Assay for Transposase Accessible Chromatin using sequencing (ATAC-seq), H3K27ac was enriched in accessible regions, consistent with the known association of H3K27ac with active promoters and enhancers (Heinz et al., 2015; Klemm et al., 2019).”
From Loss of epigenetic information as a cause of mammalian aging (2023) · cites this paper as Heinz et al., 2015
The Enhancer characteristics section (page unavailable) identifies H3K27ac as a feature of active enhancers and describes its correlation with cell-type-specific enhancer activity at an accessible locus. The passages do not establish its association with active promoters. The ChIP-seq and ATAC-seq enrichment result is presented as the citing authors’ own finding, not a result attributed to this review. (LLM, conf=0.82)
Experimental — accuracy not yet measuredDistinct sets of enhancers underlie specific gene expression patterns and allow responses unique to a cell type.
“Unique enhancer repertoires underly particular patterns of gene expression and enable cell type-specific responses (7).”
From Brain cell type–specific enhancer–promoter interactome maps and disease <b>-</b> risk association (2019) · cites this paper as [7]
Tissue-specific gene expression strongly depends on distal elements.
“The performance improvement was largest for CAGE, possibly because tissue-specific gene expression strongly depends on distal elements11.”
From Effective gene expression prediction from sequence by integrating long-range interactions (2021) · cites this paper as [11]
The activity of individual enhancers is generally cell-type-specific or condition-specific, and this specificity is a function of the expression levels of TFs able to bind to it.
“Regardless of any such mechanistic heterogeneity, a common property is that the activity of individual enhancers is generally cell-type-specific or even condition-specific99, and this specificity is a function of the expression levels of the TFs that are able to bind to it89.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [89]
Enhancers are punctate relative to broader chromatin domains, but their in vivo functionality depends on chromatin context and the trans milieu.
“Enhancers are ‘punctate’ relative to broader chromatin domains (e.g. chromosomes, topologically associating domains [G] (TADs) and sub-compartments of TADs87), but their in vivo functionality is dependent on both the chromatin context in which they reside88 and on the trans milieu (e.g. cell-type-specific TFs)89.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [89]
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- Authors
- Heinz, S., Romanoski, C. E., Benner, C., & Glass, C. K.
- Affiliations
- Salk Institute for Biological Studies (US)
- University of California San Diego (US)
- Corresponding author
- Glass, Christopher K.
- Venue
- Nature Reviews Molecular Cell Biology
- Published
- 2015-02-04
- Volume
- 16
- Issue
- 3
- Pages
- 144-154
- ISSN
- 1471-0072 (ISSN-L)
- 1471-0080
- PMC
- PMC4517609
- OpenAlex
- W2063815548
- Cited by
- 1,010
- References
- 131
- Citations by year
- 2026: 75 · 2025: 77 · 2024: 86 · 2023: 85 · 2022: 97 · 2021: 87 · 2020: 109 · 2019: 103 · 2018: 100 · 2017: 94 · 2016: 67 · 2015: 30
- FWCI
- 9.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Molecular Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (1K99HL12348)
- National Cancer Institute (R01CA173903, CA17390)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK063491, DK091183, P30DK063491, R01DK091183)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- enhancers, super-enhancers, cell type-specific gene expression, transcription factors, chromatin organization, 3D genome organization, distal regulatory elements
- MeSH terms
- Animals, Cell Differentiation, Chromatin, Enhancer Elements, Genetic, Eukaryotic Cells, Histones, Humans, Organ Specificity, Transcription Factors, Transcription, Genetic, Genome, Gene Expression Regulation, Developmental, Cell Lineage
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