Differentially Methylated Gene Expression in Professional Fighters with Repetitive Mild Traumatic Brain Injury Is...

Repetitive mild traumatic brain injury (RMTBI) and Alzheimer's disease (AD) share some pathological features, such as tau pathology, inflammation, and neurodegeneration. Tissue injury and aging are linked to cellular DNA methylation alterations in the circulation, which can result in altered gene expression, making it a promising therapeutic target for dysfunctional gene expression. It is unknown whether DNA methylation and potentially related gene expression pathophysiological mechanisms are shared between athletes exposed to RMTBI and AD. The aim was to explore the blood DNA methylomes and transcriptomes from a cohort of professional fighters (PFs) with RMTBI and AD to understand if there are significant differences in the DNA methylome that could potentially impact the transcriptome and thus contribute to pathophysiology in RMTBI. Given that RMTBI and AD share pathological features, it was hypothesized that RMTBI could also share DNA methylome and transcriptome features with AD. The methylomes (Infinium Human Methylation EPIC BeadChip) and transcriptomes (Illumina NovaSeq 6000) from active PFs (aPFs) or retired PFs (rPFs) were compared with AD and cognitively normal (CN) control groups. Several differentially methylated positions (DMPs) in the genome were linked to differentially expressed RNA transcripts that were unique to group comparison. Of these, MRPL53:CCDC142 identified in the young CN versus aPF comparison, as well as TAMM41 and CBFA2T3, identified in the rPF versus AD comparison, had significant differentially methylated RNA expression. Interestingly, a DNA methylation site located in the MRPL53:CCDC142 region was also associated with brain volume in an RMTBI subcohort. Distinct DNA methylation and corresponding gene expression alterations observed in the RMTBI cohort, compared with the AD cohort, suggests no shared DNA methylation pathophysiological contributors to AD and RMTBI pathobiology. This information is novel and suggests that MRPL53:CCDC142 DNA methylation could play an important, unique role in RMTBI underlying pathobiology.