Mutations of arginine 132 (R132) in the enzyme isocitrate dehydrogenase-1 (IDH1) are present in up to 86% of grade II and III gliomas and secondary glioblastoma. R132 mutations in IDH1 result in excess production of the metabolite 2-hydroxyglutarate (2HG), which could be used as a biomarker for this subset of gliomas. Here, we use optimized spectral-editing and two-dimensional (2D) correlation magnetic resonance spectroscopy (MRS) methods to unambiguously detect 2HG non-invasively in glioma patients with IDH1 mutations. By comparison, fitting of conventional 1D MR spectra can provide false-positive readouts owing to spectral overlap of 2HG and chemically similar brain metabolites, such as glutamate and glutamine. 2HG has been found also by 2D high-resolution magic angle spinning MRS performed ex vivo on a separate set of glioma biopsy samples. 2HG detection by in vivo or ex vivo MRS enabled detailed molecular characterization of a clinically important subset of human gliomas. This has implications for diagnosis as well as monitoring of treatments targeting IDH mutations.

Changes in telomere length are associated with degenerative diseases and cancer. Oxidative stress and DNA damage have been linked to both positive and negative alterations in telomere length and integrity. Here we examined how the common oxidative lesion 8-oxo-7,8-dihydro-2′-deoxyguanine (8-oxoG) regulates telomere elongation by telomerase. When present in the deoxynucleoside triphosphate pool as 8-oxodGTP, telomerase utilization of the oxidized nucleotide during telomere extension is mutagenic and terminates further elongation. Depletion of the enzyme that removes oxidized dNTPs, MTH1, increases telomere dysfunction and cell death in telomerase positive cancer cells harboring shortened telomeres. In contrast, a pre-existing 8-oxoG within the telomeric DNA sequence promotes telomerase activity by destabilizing G-quadruplex structure in the DNA. We show that the mechanism by which 8-oxoG arises in the telomere, either by insertion of oxidized nucleotides or by direct reaction with free radicals, dictates whether telomerase is inhibited or stimulated and thereby, mediates the biological outcome.

While diagnosis of PTSD is based on behavioral symptom clusters that are most directly associated with brain function, epigenetic studies of PTSD in humans to date have been limited to peripheral tissues. Animal models of PTSD have been key for understanding the epigenetic alterations in the brain most directly relevant to endophenotypes of PTSD, in particular those pertaining to fear memory and stress response. This chapter provides an overview of neuroepigenetic studies based on animal models of PTSD, with an emphasis on the effect of stress on fear memory. Where relevant, we also describe human-based studies with relevance to neuroepigenetic insights gleaned from animal work and suggest promising directions for future studies of PTSD neuroepigenetics in living humans that combine peripheral epigenetic measures with measures of central nervous system activity, structure and function.