2026/04/15 by Jonathan Rosenski, Ofra Sabag, Eitan Marcus +4 · 1 voice · 1 citation
Biochemistry, Genetics and Molecular Biology · #DNA methylation #Differentially methylated regions #Epigenetics #Epigenetics and DNA Methylation #Epigenome #Genetic variation #Methylation #RNA-Directed DNA Methylation #Reprogramming #Single-nucleotide polymorphism #Transcription factor
paper · pdf · doi:10.1038/s41467-026-71693-5
published in Nature Communications 17(1) (Nature Portfolio)
openalex created_date 2025/10/10 · openalex publication_date 2026/04/15 · openalex updated_date 2026/07/29
Abstract The mechanisms by which genetic variation shapes the epigenome across cell types and developmental stages have remained elusive. Here, we define a unifying developmental framework for DNA methylation programming, grounded in genome-wide methylation and genetic variation data from both mouse and human. In mice, we identify thousands of differentially methylated regions (DMRs) linked to sequence polymorphisms that disrupt transcription factor binding. These DMRs are programmed either during implantation or later in organogenesis, revealing two distinct periods of epigenetic regulation. Extending this logic to humans, we analyze our atlas of over 200 WGBS samples from 39 purified cell types and map 33,574 regions where common SNPs control allele-specific methylation. These include both early-established and cell-type-specific loci, many of which colocalize with eQTLs, enhancers, silencers, and disease-associated variants. Our results uncover a widespread mechanism by which genetic variation influences the regulatory landscape, linking sequence, methylation, and transcription across tissues. This cross-species atlas of sequence-dependent methylation not only clarifies the logic and timing of epigenetic programming, but also provides a foundational resource for deciphering non-coding variants in development, complex disease, and regenerative medicine.