Transcription factors read a second regulatory code in chromatin

Transcription factors (TFs) decipher gene regulatory information encoded in DNA, yet the manner in which this code is deciphered within chromatin is yet to be fully understood. Utilizing an enhanced NCAP-SELEX platform, researchers have conducted a comprehensive analysis of the nucleosomal DNA recognition landscapes of 269 human TFs.

Their findings reveal a previously unknown chromatin-dependent mode of sequence recognition: numerous TFs interpret motifs within nucleosomal DNA that differ from their standard naked-DNA binding sites. This discovery indicates that the structure of the nucleosome carries a secondary gene regulatory code within chromatin. Cryo-electron microscopy structures of TF-nucleosome complexes provide visual evidence that this second code is deciphered via a dual mechanism involving DNA deformation induced by the nucleosome and direct protein-histone interactions.

Functional studies demonstrate that these chromatin-encoded motifs enhance chromatin accessibility and trigger cell-type-specific cis-regulatory activities in living organisms. Remarkably, a single TF can utilize both its traditional and nucleosome-derived motif repertoires to regulate entirely separate physiological processes. The study's conclusions suggest that TFs interpret two distinct layers of genomic information: the fundamental DNA sequence and an additional code inscribed in the nucleosome architecture.

This dual-layered regulatory mechanism offers a significant advancement in our comprehension of TF specificity and the wiring of gene regulatory networks in multicellular organisms.