Differential expression of 5mC epigenomic regulators in Alzheimer's disease

Abstract

Background Epigenetic processes are molecular mechanisms that contribute to the pathogenesis of neurodegenerative diseases. 5-methylcytosine (5mC) and the oxidised state, 5-formilcytosine (5fC), are known transcriptional regulators moderated by sets of writer, reader, and eraser effector proteins. We propose that gene expression variation in DNA effector proteins may contribute to Alzheimer’s Disease (AD) neuropathology. We also aimed to characterize the distribution of 5fC modifications across brain regions and within cellular compartments to better understand the role of 5mC/5fC modifications in AD. Methods RNA sequencing data for 17 effector proteins obtained from the Aging, Dementia and Traumatic Brain Injury Study was analysed to assess variation in abundance of 5mC writers, readers, and erasers. Gene expression data were compared across four brain regions in 51 AD and 56 healthy control samples, and between Braak and CERAD neuropathological scales. In addition, we examined the presence and distribution of 5fC by immunofluorescence (IF) across four brain regions in sections from healthy individuals. Results Transcripts of DNA methylation writers DNMT1, DNMT3A and DNMT3B were found increased in the AD cohort across 3 brain regions, whilst the reader UHRF1 mRNA was decreased in the same assessment. GADD45B and AICDA, DNA methylation erasers, showed changes in mRNA abundance across Braak and CERAD neuropathological load groupings. IF analysis indicated 5fC modification to be highly abundant in dentate gyrus and within the cytoplasm of hippocampal mossy cells and of neurons in cortical layer III. Within neuronal cells, we observed 5fC partially colocalizing with mitochondria especially within hippocampal neurons. Conclusion Our findings indicate that changes in 5mC/5hmC/5fC effector protein expression are associated with AD and its neuropathology. The characterisation of 5fC localisation in human brain indicates high abundance within the cytoplasm of hippocampal cells suggesting that 5fC may be involved in pre- and post-transcriptional control of memory processing pathways and, when disrupted, may lead to neurodegenerative disease. References: Sanchez-Mut JV, et al. Transl Psychiatry. 2016; Miller JA, et al. Elife. 2017; Bachman, M., et al. Nat Chem Biol. 2015; Zhang Y, Zhou C. DNA Repair (Amst). 2019; Aging, Dementia and TBI Study (2017) Available from Allen Brain Atlas