Brain DNA methylomic analysis of frontotemporal lobar degeneration reveals OTUD4 in shared dysregulated signatures across pathological subtypes

Abstract

Frontotemporal lobar degeneration (FTLD) is an umbrella term describing the neuropathology of a clinically, genetically and pathologically heterogeneous group of diseases, including frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). Among the major FTLD pathological subgroups, FTLD with TDP-43 positive inclusions (FTLD-TDP) and FTLD with tau-positive inclusions (FTLD-tau) are the most common, representing about 90% of the cases. Although alterations in DNA methylation have been consistently associated with neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, little is known for FTLD and its heterogeneous subgroups and subtypes. The main goal of this study was to investigate DNA methylation variation in FTLD-TDP and FTLD-tau. We used frontal cortex genome-wide DNA methylation profiles from three FTLD cohorts (142 FTLD cases and 92 controls), generated using the Illumina 450K or EPIC microarrays. We performed epigenome-wide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differentially methylated loci across FTLD subgroups/subtypes. In addition, we used weighted gene correlation network analysis to identify co-methylation signatures associated with FTLD and other disease-related traits. Wherever possible, we also incorporated relevant gene/protein expression data. After accounting for a conservative Bonferroni multiple testing correction, the EWAS meta-analysis revealed two differentially methylated loci in FTLD, one annotated to OTUD4 (5’UTR-shore) and the other to NFATC1 (gene body-island). Of these loci, OTUD4 showed consistent upregulation of mRNA and protein expression in FTLD. In addition, in the three independent co-methylation networks, OTUD4-containing modules were enriched for EWAS meta-analysis top loci and were strongly associated with the FTLD status. These co-methylation modules were enriched for genes implicated in the ubiquitin system, RNA/stress granule formation and glutamatergic synaptic signalling. Altogether, our findings identified novel FTLD-associated loci, and support a role for DNA methylation as a mechanism involved in the dysregulation of biological processes relevant to FTLD, highlighting novel potential avenues for therapeutic development.

Distinctive cell‐free DNA methylation characterizes presymptomatic genetic frontotemporal dementia

“…This enzyme has not been previously associated with FTD; however, ubiquitin‐dependent signaling is a well‐known disease‐related process in several neurodegenerative disorders, contributing to protein degradation, regulation of neuronal function, and inflammation 60 . A recent study of brain methylation in symptomatic postmortem FTLD has also identified differential methylation of a deubiquinating enzyme ( OTUD4 ), postulating a role for methylation in key disease processes such as ubiquitin signaling 38 . Therefore, TSS hypermethylation in the presymptomatic group may indicate the occurrence of disease‐associated mechanisms at this stage.…”

“… 60 A recent study of brain methylation in symptomatic postmortem FTLD has also identified differential methylation of a deubiquinating enzyme ( OTUD4 ), postulating a role for methylation in key disease processes such as ubiquitin signaling. 38 Therefore, TSS hypermethylation in the presymptomatic group may indicate the occurrence of disease‐associated mechanisms at this stage. At the same time, presymptomatic carriers showed gene body methylation (suggesting gene upregulation) of genes involved in neuronal cellular processes when compared to symptomatic carriers, including the TARDBP and the PRKAR1B genes, both associated with FTD.…”

“…DNA methylation is an epigenetic modification regulating gene expression, cell functioning and tissue differentiation, which has been associated with the development of different diseases, 22 including neurodegenerative disorders 23–25 . Differential methylation of brain tissue, peripheral blood mononuclear cells or non‐specific blood DNA has been identified in AD 26–28 and in other types of dementia, 29,30 including FTD 31–40 . Methylation analysis can also be applied to cfDNA, to understand its tissue origin, 17–19 as shown extensively in the oncology field 41 .…”

“… 23 , 24 , 25 Differential methylation of brain tissue, peripheral blood mononuclear cells or non‐specific blood DNA has been identified in AD 26 , 27 , 28 and in other types of dementia, 29 , 30 including FTD. 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 Methylation analysis can also be applied to cfDNA, to understand its tissue origin, 17 , 18 , 19 as shown extensively in the oncology field. 41 This feature has the potential to connect cfDNA to the underlying biological processes involved in the disease, such as neurodegenerative mechanisms in FTD.…”

DNA methylation patterns in the frontal lobe white matter of multiple system atrophy, Parkinson’s disease, and progressive supranuclear palsy: A cross-comparative investigation

“…Although PD is primarily considered to be a grey matter disease, recent transcriptomic studies have revealed an upregulation in oligodendrocyte-related genes in the brain, a downregulation in the myelin genes and the oligodendrocyte development pathway in the cingulate cortex, and a loss of oligodendrocytes in post-mortem midbrain tissue in PD patients [69]. Conversely, PSP is characterized by abnormal tau protein aggregation in both grey and white matter regions, and single-nucleus RNA sequencing in the subthalamic nucleus of PSP identified specific contributions of the glial cell-types including increased EIF2 signalling, in addition to dysregulation in genes and pathways related to apoptotic regulation and autophagy signalling in astrocytes and oligodendrocytes [18, 67]. As in the case of MSA, bulk transcriptomic analysis also revealed changes in gene expression of myelin-related genes in PSP [3].…”