Differential expression of m5C RNA methyltransferase genes NSUN6 and NSUN7 in Alzheimer’s disease and Traumatic Brain Injury

Abstract

Abstract Epigenetic processes have become increasingly relevant in understanding disease modifying mechanisms. 5-methylcytosine methylation of DNA (5mC) and RNA (m5C) have functional transcriptional and RNA translational consequences and are tightly regulated by writers, readers, and erasers effector proteins. To investigate the involvement of 5mC/5hmC and m5C effector proteins contributing to the development of dementia neuropathology, RNA-sequencing data for 32 effector proteins across four brain regions was examined in 51 aged non-affected and 56 Alzheimer’s disease (AD) individuals obtained from the Aging, Dementia and Traumatic Brain Injury (TBI) study. Gene expression profiles were compared between AD and controls, neuropathological Braak and CERAD scores and in individuals with a history of TBI. We found an increase in DNA methylation writers DNMT1, DNMT3A, DNMT3B mRNA and decrease in reader UHRF1 mRNA in AD samples across three brain regions while the DNA erasers GADD45B and AICDA showed changes in mRNA abundance within neuropathological load groupings. RNA methylation writers NSUN6 and NSUN7 showed significant expression differences with AD and, along with the reader, ALYREF, differences in expression for neuropathologic ranking. A history of TBI was associated with a significant increase in the DNA readers ZBTB4 and MeCP2 (p < 0.05) and decrease in NSUN6 (p < 0.001) mRNA. These findings implicate regulation of protein pathways disrupted in AD and TBI via multiple pre- and post-transcriptional mechanisms including potentially acting upon tRNAs, enhancer RNAs, as well as nuclear-cytoplasmic shuttling and cytoplasmic translational control. The targeting of such processes provides new therapeutic avenues for neurodegenerative brain conditions.