ArticlePLoS genetics2020
Rare genetic variation at transcription factor binding sites modulates local DNA methylation profiles.
Article in PLoS genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it, 42 citations in OpenAlex.
- A systematic review of methylome-wide associations with anxiety disorders.Translational psychiatry · 2026Pooled it
- MambaCpG: an accurate model for single-cell DNA methylation status imputation using mamba.Briefings in bioinformatics · 2025Article
- ABCB1 Gene Polymorphisms and Their Contribution to Cognitive Decline in Mild Cognitive Impairment: A Next-Generation Sequencing Study.The journals of gerontology. Series A, Biological sciences and medical sciences · 2025Article
- Advancing long-read nanopore genome assembly and accurate variant calling for rare disease detection.American journal of human genetics · 2025Article
- The role of DNA methylation in chondrogenesis of human iPSCs as a stable marker of cartilage quality.Clinical epigenetics · 2024Article
- Hyper-physiologic mechanical cues, as an osteoarthritis disease-relevant environmental perturbation, cause a critical shift in set points of methylation at transcriptionally active CpG sites in neo-cartilage organoids.Clinical epigenetics · 2024Article
- Integrative computational analyses implicate regulatory genomic elements contributing to spina bifida.Genetics in medicine open · 2024Article
- Characterizing genetic variation in the regulation of the ER stress response through computational and cis-eQTL analyses.G3 (Bethesda, Md.) · 2023Article
- Article
- The functional impact of rare variation across the regulatory cascade.Cell genomics · 2023Article
- Identification of mammalian transcription factors that bind to inaccessible chromatin.Nucleic acids research · 2023Article
- DNA methylation entropy is associated with DNA sequence features and developmental epigenetic divergence.Nucleic acids research · 2023Article
- Translating non-coding genetic associations into a better understanding of immune-mediated disease.Disease models & mechanisms · 2023Review
- Epigenetic and Genetic Population Structure is Coupled in a Marine Invertebrate.Genome biology and evolution · 2023Article
- Genome-wide evaluation of the effect of short tandem repeat variation on local DNA methylation.Genome research · 2023Article
- Downregulation of Circulating Hsa-miR-200c-3p Correlates with Dyslipidemia in Patients with Stable Coronary Artery Disease.International journal of molecular sciences · 2023Article
- CRISPR-Cas9-mediated functional dissection of the foxc1 genomic region in zebrafish identifies critical conserved cis-regulatory elements.Human genomics · 2022Article
- Epigenomic Approaches for the Diagnosis of Rare Diseases.Epigenomes · 2022Review
- Pioneer transcription factors are associated with the modulation of DNA methylation patterns across cancers.Epigenetics & chromatin · 2022Article
- Pollution induces epigenetic effects that are stably transmitted across multiple generations.Evolution letters · 2022Article
Corrections and comments
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Authors and funding
21 authors at 13 institutions in 2 countries.
Funding
Abstract
Although DNA methylation is the best characterized epigenetic mark, the mechanism by which it is targeted to specific regions in the genome remains unclear. Recent studies have revealed that local DNA methylation profiles might be dictated by cis-regulatory DNA sequences that mainly operate via DNA-binding factors. Consistent with this finding, we have recently shown that disruption of CTCF-binding sites by rare single nucleotide variants (SNVs) can underlie cis-linked DNA methylation changes in patients with congenital anomalies. These data raise the hypothesis that rare genetic variation at transcription factor binding sites (TFBSs) might contribute to local DNA methylation patterning. In this work, by combining blood genome-wide DNA methylation profiles, whole genome sequencing-derived SNVs from 247 unrelated individuals along with 133 predicted TFBS motifs derived from ENCODE ChIP-Seq data, we observed an association between the disruption of binding sites for multiple TFs by rare SNVs and extreme DNA methylation values at both local and, to a lesser extent, distant CpGs. While the majority of these changes affected only single CpGs, 24% were associated with multiple outlier CpGs within ±1kb of the disrupted TFBS. Interestingly, disruption of functionally constrained sites within TF motifs lead to larger DNA methylation changes at nearby CpG sites. Altogether, these findings suggest that rare SNVs at TFBS negatively influence TF-DNA binding, which can lead to an altered local DNA methylation profile. Furthermore, subsequent integration of DNA methylation and RNA-Seq profiles from cardiac tissues enabled us to observe an association between rare SNV-directed DNA methylation and outlier expression of nearby genes. In conclusion, our findings not only provide insights into the effect of rare genetic variation at TFBS on shaping local DNA methylation and its consequences on genome regulation, but also provide a rationale to incorporate DNA methylation data to interpret the functional role of rare variants.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.