Managing stress granule disassembly with ubiquitin and its cousin

Müller, Stefan

doi:10.1038/s41392-021-00782-2

Cited by 2 publications

(2 citation statements)

References 5 publications

(7 reference statements)

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“…Notably, similarly to TDP-43 [ 6 ], OTUD4 was shown to be important in the correct formation of stress granules [ 20 ]. Indeed, there is much evidence as to the importance of the ubiquitin system in the functioning of stress granules [ 37 , 56 , 78 ]. The hypomethylation of the 5’UTR region of OTUD4 (cg21028777), which was observed as the top hit from the FTLD EWAS meta-analysis, and the inclusion of this CpG in three modules where decreased methylation was associated with increased risk of FTLD indicates that decreased methylation of this gene might be involved in the pathogenesis of FTLD.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2023

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Notably, similarly to TDP-43 [6], OTUD4 was shown to be important in the correct formation of stress granules [20]. Indeed, there is much evidence as to the importance of the ubiquitin system in the functioning of stress granules [36, 55, 77]. The hypomethylation of the 5’UTR region of OTUD4 (cg21028777), which was observed as the top hit from the FTLD EWAS meta-analysis, and the inclusion of this CpG in three modules where decreased methylation was associated with increased risk of FTLD indicates that decreased methylation of this gene might be involved in the pathogenesis of FTLD.…”

Section: Discussionmentioning

confidence: 99%

Brain DNA methylomic analysis of frontotemporal lobar degeneration revealsOTUD4in shared dysregulated signatures across pathological subtypes

Fodder

Murthy

Rizzu

et al. 2022

Preprint

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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, namely Alzheimer’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 (228 individuals), generated using the Illumina 450K or EPIC arrays. We performed epigenomewide association studies (EWAS) for each cohort followed by meta-analysis to identify shared differential methylated loci across FTLD subgroups/subtypes. Additionally, 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. The EWAS meta-analysis revealed four differentially methylated loci in FTLD, some of which showed altered gene and protein expression in FTLD. Two of the meta-analysis hits,OTUD4andCEBPZ, were found to be co-methylated within signatures strongly associated with FTLD. These signatures 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.

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Managing stress granule disassembly with ubiquitin and its cousin

Cited by 2 publications

References 5 publications

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

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

Brain DNA methylomic analysis of frontotemporal lobar degeneration revealsOTUD4in shared dysregulated signatures across pathological subtypes

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