5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Diagnostic Biomarkers for Late-Onset Alzheimer’s Disease

Abstract

Background: 5-Hydroxymethylcytosine (5hmC) is an epigenetic DNA modification that is highly abundant in central nervous system. It has been reported that DNA 5hmC dysregulation play a critical role in Alzheimer’s disease (AD) pathology. Changes in 5hmC signatures can be detected in circulating cell-free DNA (cfDNA), which has shown potential as a non-invasive liquid biopsy material. Objective: However, the genome-wide profiling of 5hmC in cfDNA and its potential for the diagnosis of AD has not been reported to date. Methods: We carried out a case-control study and used a genome-wide chemical capture followed by high-throughput sequencing to detect the genome-wide profiles of 5hmC in human cfDNA and identified differentially hydroxymethylated regions (DhMRs) in late-onset AD patients and the control. Results: We discovered significant differences of 5hmC enrichment in gene bodies which were linked to multiple AD pathogenesis-associated signaling pathways in AD patients compared with cognitively normal controls, indicating they can be well distinguished from normal controls by DhMRs in cfDNA. Specially, we identified 7 distinct genes (RABEP1, CPNE4, DNAJC15, REEP3, ROR1, CAMK1D, and RBFOX1) with predicting diagnostic potential based on their significant correlations with MMSE and MoCA scores of subjects. Conclusion: The present results suggest that 5hmC markers derived from plasma cfDNA can served as an effective, minimally invasive biomarkers for clinical auxiliary diagnosis of late-onset AD.

Differential expression of m5C RNA methyltransferase genes NSUN6 and NSUN7 in Alzheimer’s disease and traumatic brain injury

“…However, these reports mostly come from candidate gene studies or methylation array studies which examine pre-selected, known CpG sites often preferentially located within promoter regions [72][73][74]. To date, very few studies have performed hypothesis-free bisulphite DNA sequencing and hence have comprehensively examined, at a base resolution, mCG/mCH or 5hmC sites in individuals with dementia or TBI [75,76]. As yet, no studies have assessed single-base transcriptome-wide mRNA m 5 C methylation in cohorts with neurodegenerative diseases.…”

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

“…However, these reports mostly come from candidate gene studies or methylation array studies which examine preselected, known CpG sites often preferentially located within promoter regions [72][73][74]. To date, very few studies have performed hypothesis-free bisulphite DNA sequencing and hence have comprehensively examined, at a base resolution, mCG/mCH or 5hmC sites in individuals with dementia or TBI [75,76]. As yet, no studies have assessed single base transcriptome-wide mRNA m 5 C methylation in cohorts with neurodegenerative diseases.…”

5-Hydroxymethylcytosine: the many faces of the sixth base of mammalian DNA

“…101,[202][203][204] Besides widely attested links between hmC and cancer, the clinical relevance of tissuespecific hmC monitoring was demonstrated for other complex diseases, for example in non-invasive diagnostics of fetal Down syndrome, Alzheimer disease, and Type 2 diabetes. 105,205,206 In addition to its value as a disease marker, hmC may find some therapeutic value. As mentioned above, cells deploy a twotier safeguarding system to avoid sporadic incorporation of the modified nucleosides in DNA via the nucleotide salvage pathway (Fig.…”