A Cold Spring Harbor Laboratory-led team describes regulatory changes suspected of contributing to pancreatic cancer. Using organoid cultures developed from paired primary and metastatic pancreatic ductal adenocarcinoma tumors in mouse models, the researchers did mouse re-transplant, RNA sequencing, chromatin immunoprecipitation sequencing, and other experiments to assess genome-wide enhancer patterns as mouse pancreatic tumors progressed. Based on their results, the authors propose a role for the developmental transcription factor FOXA1 in enhancer reprogramming, apparently leading to more aggressive and invasive pancreatic cancer cells. "Collectively," they write, "our findings suggest that reprogramming of the enhancer landscape can promote the acquisition of metastatic traits."
Researchers in the US and Russia explore the metabolic consequences of late-onset Alzheimer's disease-associated variants in a microglia cell surface receptor-coding gene called TREM2. The team used mass spectrometry-based metabolomic profiling, RNA sequencing, and other approaches in mouse model of Alzheimer's disease to take a closer look at the microglial autophagy it detected in mice and in Alzheimer's disease-affected humans with risky TREM2 variants. With these and other experiments, the authors tracked down metabolic signaling shifts in microglia when Alzheimer's disease-related TREM2 variants were present, pointing to a TREM2 role in normal microglia metabolic maintenance.
Finally, a team from the US and Singapore report on findings from a study that used an RNA targeting CRISPR-Cas9 system to target and thwart the sorts of toxic microsatellite repeat expansions behind conditions such as muscular dystrophy and Huntington's disease in human cells. In their proof-of-principle experiments, researchers demonstrated that they could use a version of nuclease-lacking Cas9 fused to an RNA endonuclease to target microsatellite repeat expansion RNAs and prompt their subsequent degradation. "[O]ur findings indicate the potential of a new therapeutic mechanism for the CRISPR/Cas9 system among a class of neurological and neuromuscular conditions linked to microsatellite repeat expansions," the authors write.