Cooperativity enables widespread role of low-affinity motifs in chromatin accessibility and increases regulatory potential
Year: 2026
Type: article
Abstract: Low-affinity transcription-factor (TF) motifs are an important element of the cis-regulatory code, yet they are notoriously difficult to map and mechanistically incompletely understood, limiting our ability to interpret non-coding variation in development, evolution, and disease. Here, we investigate their role in pioneering and leverage sequence-to-profile models of chromatin accessibility in mouse embryonic stem cells to reliably map and interpret low-affinity motifs across the genome. We find that low-affinity motifs have outsized effects by cooperating with nearby motifs through intra-nucleosomal soft syntax. By modeling nucleosome-mediated cooperativity with a kinetic model, we discover and validate that pioneer cooperativity makes a motif operate at higher pioneering ranges across changing TF concentrations, thereby raising the regulatory potential. These results show that low-affinity motifs can be accurately mapped, shape the properties of developmental enhancers, and likely play a widespread role in fine-tuning enhancers during evolution.
Source: Cell Genomics
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $8,900
Funders: Foundation for the National Institutes of Health, Stowers Institute for Medical Research, Ministerio de Ciencia, Innovación y Universidades, Centres de Recerca de Catalunya, European Commission, Generalitat de Catalunya, National Institutes of Health, European Regional Development Fund, Agencia Estatal de Investigación, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NextGenerationEU
Awards: G1105844351, G1482478015, G2064873908, Investigating how transcription factors cooperate and overcome the enhancer nucleosome barrier during embryonic patterning, G2462415295, G3005324705, G318412399, G3392608217, G3546882995, G3979509674, G410571670, G4212894969, G4228227490, G451917667, A transposase system for integrative ChIP-exo and ATAC-seq analysis at single-cell resolution, G491712853, G4993905653, G5539308778, G5635532810, G5967599077, G6033112984, G6123788462, G6520718613, G6656126374, G7395345766, G7805626310, G7863371703, G8497050386, G8667377315
OpenAlex ID: W7204162191