Deciphering the mechanical code of the genome and epigenome.

Diverse DNA-deforming processes are impacted by the local mechanical and structural properties of DNA, which in turn depend on local sequence and epigenetic modifications. Deciphering this mechanical code (that is, this dependence) has been challenging due to the lack of high-throughput experimental methods. Here we present a comprehensive characterization of the mechanical code. Utilizing high-throughput measurements of DNA bendability via loop-seq, we quantitatively established how the occurrence and spatial distribution of dinucleotides, tetranucleotides and methylated CpG impact DNA bendability. We used our measurements to develop a physical model for the sequence and methylation dependence of DNA bendability. We validated the model by performing loop-seq on mouse genomic sequences around transcription start sites and CTCF-binding sites. We applied our model to test the predictions of all-atom molecular dynamics simulations and to demonstrate that sequence and epigenetic modifications can mechanically encode regulatory information in diverse contexts.

Measuring DNA mechanics on the genome scale.

Mechanical deformations of DNA such as bending are ubiquitous and have been implicated in diverse cellular functions1. However, the lack of high-throughput tools to measure the mechanical properties of DNA has limited our understanding of how DNA mechanics influence chromatin transactions across the genome. Here we develop 'loop-seq'-a high-throughput assay to measure the propensity for DNA looping-and determine the intrinsic cyclizabilities of 270,806 50-base-pair DNA fragments that span Saccharomyces cerevisiae chromosome V, other genomic regions, and random sequences. We found sequence-encoded regions of unusually low bendability within nucleosome-depleted regions upstream of transcription start sites (TSSs). Low bendability of linker DNA inhibits nucleosome sliding into the linker by the chromatin remodeller INO80, which explains how INO80 can define nucleosome-depleted regions in the absence of other factors2. Chromosome-wide, nucleosomes were characterized by high DNA bendability near dyads and low bendability near linkers. This contrast increases for deeper gene-body nucleosomes but disappears after random substitution of synonymous codons, which suggests that the evolution of codon choice has been influenced by DNA mechanics around gene-body nucleosomes. Furthermore, we show that local DNA mechanics affect transcription through TSS-proximal nucleosomes. Overall, this genome-scale map of DNA mechanics indicates a 'mechanical code' with broad functional implications.

Water-Cooled Radiofrequency Provides Pain Relief, Decreases Disability, and Improves Quality of Life in Chronic Knee Osteoarthritis.

Chronic osteoarthritis (OA) is a widespread source of pain and disability and represents a growing economic burden across aging populations. Representing a major focus of arthritis care, OA of the knee is especially concerning as it has the potential to restrict mobility and significantly impair quality of life. Chronic OA is often poorly managed both pharmacologically and nonpharmacologically, with surgical management representing the definitive treatment. Those who are not surgical candidates or simply opt for minimally invasive treatments are usually faced with a lack of alternatives. An additional treatment presents itself in the form of water-cooled radiofrequency ablation, which involves the use of thermal lesions to interrupt the active pain pathways. An 81-year-old woman with bilateral severe knee OA was initially seen and evaluated in an outpatient physiatry clinic after multiple previous workups of her ongoing knee pain. With a known diagnosis of end-stage knee OA, the patient chose to proceed with bilateral water-cooled radiofrequency ablation. At 6 weeks and 3 months after the procedure, the patient maintained adequate levels of pain relief, markedly improved function, and enhanced quality of life. Water-cooled radiofrequency ablation has the potential to create lasting pain relief and with minimal adverse effects in patients with chronic knee OA.