LAUSR

Summary Gene regulation in higher organisms involves a sophisticated interplay between genetic and epigenetic mechanisms. Despite advances, the logic in selective usage of certain genomic regions as regulatory elements remains unclear. Here we show that the inherent biophysical properties of the DNA encode epigenetic state and the underlying regulatory potential. We find that the propeller twist (ProT) level is indicative of genomic location of the regulatory elements, their strength, the affinity landscape of transcription factors, and distribution in the nuclear 3D space. We experimentally show that ProT levels confer increased DNA flexibility and surface accessibility, and thus potentially primes usage of high ProT regions as regulatory elements. ProT levels also correlate with occurrence and phenotypic consequences of mutations. Interestingly, cell-fate switches involve a transient usage of low ProT regulatory elements. Altogether, our work provides unprecedented insights into the gene regulatory landscape encoded in the DNA biophysical features.