Year: 2026
Type: preprint
Abstract: Transcription factors (TFs) decode gene regulatory information written in DNA, yet how this vocabulary is interpreted within chromatin remains largely unexplored. Here, using an upgraded NCAP-SELEX platform, we systematically map the nucleosomal DNA recognition landscapes of 269 human TFs. We uncover a widespread, chromatin-dependent mode of sequence recognition: many TFs recognize motifs on nucleosomal DNA that are distinct from their canonical naked-DNA binding sites, revealing that nucleosome architecture encodes a second gene regulatory code in chromatin. Cryo-electron microscopy structures of TF-nucleosome complexes demonstrate that this second code is read through a combination of nucleosome-induced DNA deformation and direct protein-histone contacts. Functional analyses show that these chromatin-encoded motifs actively promote chromatin accessibility and drive cell-type-specific cis-regulatory activity in vivo . Strikingly, a single TF can deploy its canonical and nucleosome-derived motif repertoires to partition and govern entirely distinct physiological programs. Together, our findings establish that TFs interpret two complementary layers of genomic information: the primary DNA sequence and a second code written into the nucleosome architecture. This chromatin-encoded layer of regulatory information fundamentally expands our understanding of how TF specificity is achieved and how gene regulatory networks are wired in multicellular organisms.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214123713