Biology subjects

Gotkine, M.

Publications and source records attributed to Gotkine, M..

4 recordsLinked to original sources

bioRxiv2026

Sex-dependent DNA methylation in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) shows well-established sex differences in incidence, age at onset and progression, but their biological basis is unclear. We hypothesised that the DNA methylation changes associated with ALS differ between the sexes, which would point to sex-specific disease processes. To test this, we performed a blood-based epigenome-wide association meta-analysis of ALS cases and controls from Project MinE, an international ALS genomics consortium, and an independent Australian cohort, comprising 8,946 individuals after quality control (5,129 males and 3,817 females; 8,942 with complete covariates in the primary models). We analysed 781,648 autosomal CpGs using complementary sex-stratified case-control models and an ALS-by-sex interaction model that directly tested whether ALS-associated methylation effects differed by sex. Sex-stratified analyses identified no genome-wide significant differences between male and female ALS effects. In contrast, interaction testing identified seven robust sex-dependent ALS-associated differentially methylated positions (P < 9 x 10-8), mapping to KCNQ1, ADPRH, HLA-F, GHRLOS, IRF5, RAD51B and one intergenic region. The strongest signal was at KCNQ1 (P = 3.1 x 10-9). Six of the seven remained genome-wide significant in a four-stratum sensitivity analysis, and none was detected in previous conventional ALS or population sex-associated methylation analyses. Together, these findings suggest a distinct sex-conditional component of the ALS blood methylome, implicating immune, metabolic and ion-channel loci and providing new candidates for investigating biological heterogeneity between males and females with ALS.

genomics↗

bioRxiv2024

Sex-specific DNA methylation differences in Amyotrophic lateral sclerosis

Sex is an important covariate in all genetic and epigenetic research due to its role in the incidence, progression and outcome of many phenotypic characteristics and human diseases. Amyotrophic lateral sclerosis (ALS) is a motor neuron disease with a sex bias towards higher incidence in males. Here, we report for the first time a blood-based epigenome-wide association study meta-analysis in 9274 individuals after stringent quality control (5529 males and 3975 females). We identified a total of 226 ALS saDMPs (sex-associated DMPs) annotated to a total of 159 unique genes. These ALS saDMPs were depleted at transposable elements yet significantly enriched at enhancers and slightly enriched at 3UTRs. These ALS saDMPs were enriched for transcription factor motifs such as ESR1 and REST. Moreover, we identified an additional 10 genes associated with ALS saDMPs through chromatin loop interactions, suggesting a potential regulatory role for these saDMPs on distant genes. Furthermore, we investigated the relationship between DNA methylation at specific CpG sites and overall survival in ALS using Cox proportional hazards models. We identified two ALS saDMPs, cg14380013 and cg06729676, that showed significant associations with survival. Overall, our study reports a reliable catalogue of sex-associated ALS saDMPs in ALS and elucidates several characteristics of these sites using a large-scale dataset. This resource will benefit future studies aiming to investigate the role of sex in the incidence, progression and risk for ALS.

genomics↗

bioRxiv2023

SMCHD1 loss triggers DUX4 expression by disrupting splicing in FSHD2

Structural Maintenance of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1) is a non-canonical member of the structural maintenance of chromosomes (SMC) protein family involved in the regulation of chromatin structure, epigenetic regulation, and transcription. Mutations in SMCHD1 cause facioscapulohumeral muscular dystrophy type 2 (FSHD2), a rare genetic disorder characterized by progressive muscle weakness and wasting, believed to be caused by aberrant expression of DUX4 in muscle cells. Here we suggest a new role for SMCHD1 as a regulator of alternative splicing in various cell types. We demonstrate how SMCHD1 mutations cause splicing alterations of DNA Methyltransferase 3 Beta DNMT3B which can lead to hypomethylation, DUX4 expression, and FSHD pathogenesis. Analyzing RNA-seq data from muscle biopsies of FSHD2 patients and Smchd1 knocked out cells, we found that hundreds of genes were mis-spliced upon loss of SMCHD1. At least 20% of mis-spliced genes were associated with abnormalities of the musculature. Moreover, we show that mis-spliced exons tend to be bound by SMCHD1, and these exons demonstrate a slower elongation rate, suggesting SMCHD1 binding promotes exon exclusion by slowing RNA polymerase II (RNAPII). Specifically, we discovered that SMCHD1 mutations promote the splicing of the DNMT3B1 isoform of DNMT3B by perturbing RNAPII elongation rate and recruitment of the splicing factor RBM5. The mis-splicing of DNMT3B leads to hypomethylation of the D4Z4 region and DUX4 overexpression. These results suggest that mis-splicing by SMCHD1 may play a major role in FSHD2 pathogenesis by promoting the mis-splicing of different targets including DNMT3B, and highlight the potential for targeting splicing as a therapeutic strategy for this disorder. Significance statementOur study sheds light on how the loss of SMCHD1 drives the pathogenesis of facioscapulohumeral muscular dystrophy (FSHD), a rare genetic disorder characterized by muscle weakness and wasting. We found that SMCHD1 mutations led to changes in splicing of hundreds of genes, 20% of which were related to muscle abnormalities. We found that SMCHD1 tends to bind mis-spliced exons and that its binding slows down the elongation rate of RNA polymerase II often leading to the exclusion of the exon. One of these targets is DNA Methyltransferase 3 Beta (DNMT3B), and we show that the isoform promoted by SMCHD1 mutations leads to hypomethylation of a repeat region near DUX4 and to DUX4 overexpression, a known cause for FSHD. Our results provide insight into the molecular mechanisms underlying this disorder, and suggest splicing modulation as a therapeutic strategy for FSHD.

genomics↗

bioRxiv2018

The Project MinE databrowser: bringing large-scale whole-genome sequencing in ALS to researchers and the public.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative disease affecting 1 in 350 people. The aim of Project MinE is to elucidate the pathophysiology of ALS through whole-genome sequencing at least 15,000 ALS patients and 7,500 controls at 30X coverage. Here, we present the Project MinE data browser (databrowser.projectmine.com). a unique and intuitive one-stop, open-access server that provides detailed information on genetic variation analyzed in a new and still growing set of 4,366 ALS cases and 1,832 matched controls. Through its visual components and interactive design, the browser specifically aims to be a resource to those without a biostatistics background and allow clinicians and preclinical researchers to integrate Project MinE data into their own research. The browser allows users to query a transcript and immediately access a unique combination of detailed (meta)data, annotations and association statistics that would otherwise require analytic expertise and visits to scattered resources.

genomics↗