Dynamic antagonism between key repressive pathways maintains the placental epigenome

DNA and Histone 3 Lysine 27 methylation typically function as repressive modifications and operate within distinct genomic compartments. In mammals, the majority of the genome is kept in a DNA methylated state, whereas the Polycomb repressive complexes regulate the unmethylated CpG-rich promoters of developmental genes. In contrast to this general framework, the extra-embryonic lineages display non-canonical, globally intermediate DNA methylation levels, including disruption of local Polycomb domains. Here, to better understand this unusual landscape’s molecular properties, we genetically and chemically perturbed major epigenetic pathways in mouse trophoblast stem cells. We find that the extra-embryonic epigenome reflects ongoing and dynamic de novo methyltransferase recruitment, which is continuously antagonized by Polycomb to maintain intermediate, locally disordered methylation. Despite its disorganized molecular appearance, our data point to a highly controlled equilibrium between counteracting repressors within extra-embryonic cells, one that can seemingly persist indefinitely without bistable features typically seen for embryonic forms of epigenetic regulation

Multi-energy spectral photon-counting computed tomography (MARS) for detection of arthroplasty implant failure

To determine whether state-of-the-art multi-energy spectral photon-counting computed tomography (MARS) can detect knee arthroplasty implant failure not detected by standard pre-operative imaging techniques. A total knee arthroplasty (TKA) removed from a patient was reviewed. The extracted prosthesis [NexGen Legacy Posterior Stabilized (LPS) TKA] was analyzed as were pre-operative imaging examination and compared with a MARS-CT examination obtained of the extracted TKA prosthesis. Radiographs, fuoroscopy, ultrasound and MRI preoperatively did not reveal the cause of the implant failure. MARS CT images of the extracted prosthesis clearly showed the presence of posteromedial polyethylene and tibial tray wear which is compatible with the clinical appearance of the extracted TKA. MARS can identify polyethylene insert and metallic tibial tray wear as a cause of TKA failure, that could not be identifed with on standard pre-operative imaging. Although clinical MARS CT system is still under development, this case does illustrate its potential clinical usefulness. This is the frst study to document how MARS CT imaging can detect orthopedic implant failure not detected by standard current imaging techniques. This system has a potential clinical application in orthopedic patients

Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress

Genotoxic therapy such as radiation serves as a frontline cancer treatment, yet acquired resistance that leads to tumor reoccurrence is frequent. We found that cancer cells maintain viability during irradiation by reversibly increasing genome-wide DNA breaks, thereby limiting premature mitotic progression. We identify caspase-activated DNase (CAD) as the nuclease inflicting these de novo DNA lesions at defined loci, which are in proximity to chromatin-modifying CCCTC-binding factor (CTCF) sites. CAD nuclease activity is governed through phosphorylation by DNA damage response kinases, independent of caspase activity. In turn, loss of CAD activity impairs cell fate decisions, rendering cancer cells vulnerable to radiation-induced DNA double-strand breaks. Our observations highlight a cancer-selective survival adaptation, whereby tumor cells deploy regulated DNA breaks to delimit the detrimental effects of therapy-evoked DNA damage