Abstract
The Human Genome Project marked a major milestone in the scientific community as it unravelled the ~3 billion bases that are central to crucial aspects of human life. Despite this achievement, it only scratched the surface of understanding how each nucleotide matters, both individually and as part of a larger unit. Beyond the coding genome, which comprises only ~2% of the whole genome, scientists have realized that large portions of the genome, not known to code for any protein, were crucial for regulating the coding genes. These large portions of the genome comprise the ‘non-coding genome’. The history of gene regulation mediated by proteins that bind to the regulatory non-coding genome dates back many decades to the 1960s. However, the original definition of ‘enhancers’ was first used in the early 1980s. In this Review, we summarize benchmark studies that have mapped the role of cardiac enhancers in disease and development. We highlight instances in which enhancer-localized genetic variants explain the missing link to cardiac pathogenesis. Finally, we inspire readers to consider the next phase of exploring enhancer-based gene therapy for cardiovascular disease.
Key points
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Genome-wide chromatin-profiling technologies have facilitated the mapping of regulatory regions in the cardiac genome, with high resolution and high throughput.
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These assays have revealed how enhancer dynamics regulate or associate with transcriptomic changes observed in cardiac development and disease.
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Genetic variants in regulatory enhancers can be implicated in disease pathogenesis and can help to identify pathways in disease development.
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Targeting enhancers might open up new avenues for cardiac therapy.
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C.G.A.-N. and R.S.Y.F. researched data for the article. C.G.A.-N., M.C.J.L. and R.S.Y.F. contributed to discussion of the content. C.G.A.-N., M.C.J.L., A.D. and R.S.Y.F. wrote the article. All of the authors reviewed and/or edited the manuscript before submission.
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Nature Reviews Cardiology thanks T. Pedrazzini and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Related links
Cis-element Atlas: http://www.catlas.org/humantissue/#!/
ENCODE: https://www.encodeproject.org/
Epigenome Browser: http://epigenomegateway.wustl.edu/
EpiMap Repository: http://compbio.mit.edu/epimap/
FANTOM: https://fantom.gsc.riken.jp/
IHEC: http://ihec-epigenomes.org/
The Ensembl Regulatory Build: http://www.ensembl.org/info/genome/funcgen/regulatory_build.html
TRANSFAC: https://genexplain.com/transfac/
Vista Enhancer Browser: https://enhancer.lbl.gov/
Glossary
- Transcription factors
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Proteins that bind to DNA, often by recognizing short DNA (motif) sequences that are typically 6–10 bp. Pioneering transcription factors recruit other DNA-binding proteins (co-activators or co-repressors) and contribute to the regulation of RNA transcription.
- Nucleosome
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The basic structural unit of DNA packaging in eukaryotes, comprising a segment of DNA wrapped around a core of histone proteins.
- Histone acetyltransferase
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A family of enzymes that transfers acetyl groups to lysine residues of histone proteins.
- Histone modifications
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Covalent post-translational modifications of histone proteins, including histone acetylation, methylation and phosphorylation. H3K27ac and H3K4me1 are the histone modifications most commonly associated with enhancers.
- Enhancer RNA
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(eRNA). A non-coding RNA molecule transcribed from the DNA sequence of enhancer loci.
- Super-enhancers
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Clusters of enhancers, often bound by many transcription factors, and are usually specifically important for cell identity.
- Expression quantitative trait loci
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DNA variants that correlate with changes in gene expression.
- Histone acetylation quantitative trait loci
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DNA variants within the enhancer peaks that correlate with changes in the acetylation peak height.
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Anene-Nzelu, C.G., Lee, M.C.J., Tan, W.L.W. et al. Genomic enhancers in cardiac development and disease. Nat Rev Cardiol 19, 7–25 (2022). https://doi.org/10.1038/s41569-021-00597-2
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DOI: https://doi.org/10.1038/s41569-021-00597-2
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