High-resolution genome-wide functional dissection of transcriptional regulatory regions and nucleotides in human
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Abstract
Genome-wide epigenomic maps have revealed millions of putative enhancers and promoters, but experimental validation of their function and high-resolution dissection of their driver nucleotides remain limited. Here, we present HiDRA (High-resolution Dissection of Regulatory Activity), a combined experimental and computational method for high-resolution genome-wide testing and dissection of putative regulatory regions. We test ~7 million accessible DNA fragments in a single experiment, by coupling accessible chromatin extraction with self-transcribing episomal reporters (ATAC-STARR-seq). By design, fragments are highly overlapping in densely-sampled accessible regions, enabling us to pinpoint driver regulatory nucleotides by exploiting differences in activity between partially-overlapping fragments using a machine learning model (SHARPR-RE). In GM12878 lymphoblastoid cells, we find ~65,000 regions showing enhancer function, and pinpoint ~13,000 high-resolution driver elements. These are enriched for regulatory motifs, evolutionarily-conserved nucleotides, and disease-associated genetic variants from genome-wide association studies. Overall, HiDRA provides a high-throughput, high-resolution approach for dissecting regulatory regions and driver nucleotides.
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Histone modification and cofactor binding are enriched but not completely predictive of enhancer activity.
“Although enriched, histone modification and cofactor binding is not completely predictive of enhancer activity54,58,72,77,105.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [77]
In Results, “HiDRA elements are enriched in promoters and enhancers” (page unavailable), the paper reports enrichment of active-enhancer-associated histone marks in active fragments. The Introduction and “Regulatory activity outside promoters and enhancers” explain why epigenomic marks do not fully predict reporter activity. The paper discusses enrichment of transcription-factor motifs and binding, but the available passages do not establish the claim specifically for cofactor binding. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIt remains possible that many biochemically identified enhancers may not be enhancing transcription of anything.
“In fact, it remains entirely possible that many biochemically identified enhancers may not be enhancing transcription of anything77.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [77]
The Introduction (page unavailable) says many regions identified by epigenomic marks do not drive reporter-gene expression, supporting doubt that every biochemically identified enhancer is functional. A negative reporter assay does not establish that those regions enhance no transcription in any context, so the broader possibility in the claim is not fully supported. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMPRAs have been applied to assess biochemically annotated candidate enhancers, candidate enhancers harbouring variants that potentially mediate eQTLs, and even scans of the entire human genome.
“MPRAs have been applied to assess biochemically annotated candidate enhancers77,176-178, candidate enhancers harbouring variants that potentially mediate eQTLs179-182, and even scans of the entire human genome108,183.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [77]
This source is cited for the genome-wide-scan portion of the sentence. The Introduction reports a genome-wide HiDRA assay, but says its approximately 7 million tested fragments were preferentially selected from accessible chromatin in GM12878 cells. The Results (‘HiDRA experimental method overview’; page unavailable) likewise say the library targeted accessible DNA rather than randomly sampling the entire genome, so the claim overstates its scope. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMassively parallel reporter assays and CRISPR genome editing have matured rapidly to enable functional characterization of targeted sequence perturbations at scale.
“To address this, there has been rapid maturation of technologies, such as massively parallel reporter assays121–123 and CRISPR genome editing, to support functional characterization of targeted sequence perturbations at scale.”
From A brief history of human disease genetics (2020) · cites this paper as [123]
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- Authors
- Wang, X., He, L., Goggin, S. M., Saadat, A., Wang, L., Sinnott-Armstrong, N., Claussnitzer, M., & Kellis, M.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Claussnitzer, Melina
- Kellis, Manolis
- ORCID
- Venue
- Nature Communications
- Published
- 2018-12-19
- Volume
- 9
- Issue
- 1
- Pages
- 5380-5380
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6300699
- OpenAlex
- W2903823332
- Cited by
- 159
- References
- 45
- Citations by year
- 2026: 5 · 2025: 16 · 2024: 27 · 2023: 18 · 2022: 18 · 2021: 23 · 2020: 30 · 2019: 12 · 2018: 7 · 2017: 3
- FWCI
- 6.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Nature
- Funders
- National Institutes of Health (GM12878, NIH-R01)
- McDonnell Center for Systems Neuroscience
- National Human Genome Research Institute (U01HG007610, R01HG008155, U01HG009088)
- National Institute of General Medical Sciences (R01GM113708)
- 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
- HIDRA, enhancer function, transcriptional regulatory sequences, chromatin accessibility, machine learning, regulatory motifs, disease-associated variants
- MeSH terms
- Gene Expression Regulation, Genetic Techniques, Humans, Regulatory Sequences, Nucleic Acid, Genome, Human, Polymorphism, Single Nucleotide, Genome-Wide Association Study
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