Three-dimensional chromatin mapping of sensory neurons reveals that promoter-enhancer looping is required for axonal regeneration.

The in vivo three-dimensional genomic architecture of adult mature neurons at homeostasis and after medically relevant perturbations such as axonal injury remains elusive. Here, we address this knowledge gap by mapping the three-dimensional chromatin architecture and gene expression program at homeostasis and after sciatic nerve injury in wild-type and cohesin-deficient mouse sensory dorsal root ganglia neurons via combinatorial Hi-C, promoter-capture Hi-C, CUT&Tag for H3K27ac and RNA-seq. We find that genes involved in axonal regeneration form long-range, complex chromatin loops, and that cohesin is required for the full induction of the regenerative transcriptional program. Importantly, loss of cohesin results in disruption of chromatin architecture and severely impaired nerve regeneration. Complex enhancer-promoter loops are also enriched in the human fetal cortical plate, where the axonal growth potential is highest, and are lost in mature adult neurons. Together, these data provide an original three-dimensional chromatin map of adult sensory neurons in vivo and demonstrate a role for cohesin-dependent long-range promoter interactions in nerve regeneration.

MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways.

MicroRNAs (miRNA) regulate fundamental biological processes, including neuronal plasticity, stress response, and survival. Here, we describe a neuroprotective function of miR-132, the miRNA most significantly downregulated in neurons in Alzheimer's disease. We demonstrate that miR-132 protects primary mouse and human wild-type neurons and more vulnerable Tau-mutant neurons against amyloid ß-peptide (Aß) and glutamate excitotoxicity. It lowers the levels of total, phosphorylated, acetylated, and cleaved forms of Tau implicated in tauopathies, promotes neurite elongation and branching, and reduces neuronal death. Similarly, miR-132 attenuates PHF-Tau pathology and neurodegeneration, and enhances long-term potentiation in the P301S Tau transgenic mice. The neuroprotective effects are mediated by direct regulation of the Tau modifiers acetyltransferase EP300, kinase GSK3ß, RNA-binding protein Rbfox1, and proteases Calpain 2 and Caspases 3/7. These data suggest miR-132 as a master regulator of neuronal health and indicate that miR-132 supplementation could be of therapeutic benefit for the treatment of Tau-associated neurodegenerative disorders.

Three-dimensional chromatin mapping of sensory neurons reveals that cohesin-dependent genomic domains are required for axonal regeneration.

The in vivo three-dimensional genomic architecture of adult mature neurons at homeostasis and after medically relevant perturbations such as axonal injury remains elusive. Here we address this knowledge gap by mapping the three-dimensional chromatin architecture and gene expression programme at homeostasis and after sciatic nerve injury in wild-type and cohesin-deficient mouse sensory dorsal root ganglia neurons via combinatorial Hi-C and RNA-seq. We find that cohesin is required for the full induction of the regenerative transcriptional program, by organising 3D genomic domains required for the activation of regenerative genes. Importantly, loss of cohesin results in disruption of chromatin architecture at regenerative genes and severely impaired nerve regeneration. Together, these data provide an original three-dimensional chromatin map of adult sensory neurons in vivo and demonstrate a role for cohesin-dependent chromatin interactions in neuronal regeneration.

Sex-Specific Differences in Patients with IDH1-Wild-Type Grade 4 Glioma in the ReSPOND Consortium.

BACKGROUND AND PURPOSE: Understanding sex-based differences in patients with glioblastoma is necessary for accurate personalized treatment planning to improve patient outcomes. Our purpose was to investigate sex-specific differences in molecular, clinical, and radiologic tumor parameters, as well as survival outcomes in patients with glioblastoma, isocitrate dehydrogenase-1 wild-type (IDH1-WT), grade 4. MATERIALS AND METHODS: Retrospective data of 1832 patients with glioblastoma, IDH1-WT with comprehensive information on tumor parameters was acquired from the Radiomics Signatures for Precision Oncology in Glioblastoma consortium. Data imputation was performed for missing values. Sex-based differences in tumor parameters, such as age, molecular parameters, preoperative Karnofsky performance score (KPS), tumor volumes, epicenter, and laterality were assessed through nonparametric tests. Spatial atlases were generated by using preoperative MRI maps to visualize tumor characteristics. Survival time analysis was performed through log-rank tests and Cox proportional hazard analyses. RESULTS: Glioblastoma was diagnosed at a median age of 64 years in women compared with 61.9 years in men (false discovery rate [FDR] = 0.003). Men had a higher KPS (above 80) as compared with women (60.4% women versus 69.7% men, FDR = 0.044). Women had lower tumor volumes in enhancing (16.7 cm3 versus 20.6 cm3 in men, FDR = 0.001), necrotic core (6.18 cm3 versus 7.76 cm3 in men, FDR = 0.001), and edema regions (46.9 cm3 versus 59.2 cm3 in men, FDR = 0.0001). The right temporal region was the most common tumor epicenter in the overall population. Right as well as left temporal lobes were more frequently involved in men. There were no sex-specific differences in survival outcomes and mortality ratios. Higher age, unmethylated O6-methylguanine-DNA-methyltransferase promoter and undergoing subtotal resection increased the mortality risk in both men and women. CONCLUSIONS: Our study demonstrates significant sex-based differences in clinical and radiologic tumor parameters of patients with glioblastoma. Sex is not an independent prognostic factor for survival outcomes and the tumor parameters influencing patient outcomes are identical for men and women.