bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2020.09.25.313197

MSH2 knock-down shows CTG repeat stability and concomitant upstream demethylation at the DMPK locus in myotonic dystrophy type 1 human embryonic stem cells

Franck, S.·BarbE, L.·Ardui, S.·De Vlaeminck, Y.·Allemeersch, J.·Dziedzicka, D.·Spits, C.·Vanroye, F.·Hilven, P.·Duque, G.·Vermeesch, J. R.·Gheldof, A.·Sermon, K. D.
View original source ↗Export metadata ↓

Abstract

Myotonic dystrophy type 1 (DM1) is caused by expansion of a CTG repeat in the DMPK gene, where expansion size and somatic mosaicism correlates with disease severity and age of onset. While it is known that the mismatch repair protein MSH2 contributes to the unstable nature of the repeat, its role on other disease-related features, such as CpG methylation upstream of the repeat, is unknown. In this study, we investigated the effect of an MSH2 knock-down (MSH2KD) on both CTG repeat dynamics and CpG methylation pattern in human embryonic stem cells (hESC) carrying the DM1 mutation. Repeat size in MSH2 wild type (MSH2WT) and MSH2KD DM1 hESC was determined by PacBio sequencing and CpG methylation by bisulfite massive parallel sequencing. We found stabilization of the CTG repeat concurrent with a gradual loss of methylation upstream of the repeat in MSH2KD cells, while the repeat continued to expand and upstream methylation remained unchanged in MSH2WT control lines. Repeat instability was re-established and biased towards expansions upon MSH2 transgenic re-expression in MSH2KD lines while upstream methylation was not consistently re-established. We hypothesize that the hypermethylation at the mutant DM1 locus is promoted by the MMR machinery and sustained by a constant DNA repair response, establishing a potential mechanistic link between CTG repeat instability and upstream CpG methylation. Our work represents a first step towards understanding how epigenetic alterations and repair pathways connect and contribute to the DM1 pathology.

Source connections

Explore related subjects

geneticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Franck, S., BarbE, L., Ardui, S., De Vlaeminck, Y., Allemeersch, J., Dziedzicka, D., Spits, C., Vanroye, F., Hilven, P., Duque, G., Vermeesch, J. R., Gheldof, A., Sermon, K. D.. 2020-09-25. MSH2 knock-down shows CTG repeat stability and concomitant upstream demethylation at the DMPK locus in myotonic dystrophy type 1 human embryonic stem cells. https://doi.org/10.1101/2020.09.25.313197

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

SARDINE unlocks EWAS summary statistics for large-scale epigenetic biomarker analysis

Epigenetic clocks are increasingly used to study biological aging, yet their interpretation and utility remain uncertain. Meanwhile, the growing wealth of epigenome-wide association study (EWAS) summary statistics remains largely untapped for evaluating these biomarkers. Here, we introduce SARDINE, a statistical framework that estimates epigenetic clock-phenotype associations using EWAS summary statistics, clock weights, and reference methylation covariance, without individual-level data. SARDINE accurately reproduced individual-level association estimates across 38 epigenetic biomarkers and four phenotypes in 15,677 individuals. Applying SARDINE to diverse EWAS datasets revealed substantial heterogeneity in biomarker associations with aging, diseases, and lifestyle factors. By transforming CpG-level EWAS results into interpretable biomarker-level associations, SARDINE unlocks a largely underutilized data resource and establishes a scalable paradigm for systematic biomarker evaluation and discovery in aging research.

genetics↗
bioRxiv2026

Deep transcriptomic analysis of molecular mediators of complex traits in heterogeneous stock (HS) rats

Rats are a powerful model organism for genome-wide association studies (GWAS) of physiological and behavioral traits. Heterogeneous Stock (HS) rats, which were created by intercrossing 8 inbred rat strains, are heavily used for this purpose because of their genetic diversity and accumulated recombinations due to over 100 generations of outbreeding, which improves mapping precision. However, functional genomics resources for post-GWAS interpretation of genomic findings have been limited. We processed 3,160 RNA-seq samples, 1,932 of which were previously unpublished, from 13 tissues as part of RatGTEx. We used Pantry to quantify six modalities of transcriptome regulation (expression, isoform ratio, intron excision ratio, alternative transcription start site (TSS), alternative poly(A), and RNA stability) in each sample, which allowed us to identify 144,876 independent quantitative trait loci (QTL) for 22,599 genes. We performed a transcriptome-wide association study (TWAS) with 19,796 unique genes across tissues and transcriptional modalities and 308 traits collected from 14 studies using FUSION, which identified 7,473 significant gene-trait associations. This work presents a significant expansion of the RatGTEx resource in terms of samples, modes of transcriptome regulation, and genetic analyses. Our findings provide molecular evidence for the involvement of specific genes in mediating GWAS signals through a range of transcriptome regulatory mechanisms. These gene-to-phenotype relationships can be easily applied to genetic analyses in humans and other species. Further experiments can use this evidence to confirm these molecular mediators and target them for the treatment of behavioral and physiological traits and disorders. To facilitate use of these results, we have updated results on RatGTEx.org and provided a new interactive TWAS web portal (twas.ratgtex.org).

genetics↗
bioRxiv2026

Genomic and Epigenomic Relationships Capture Different Patterns of Genotype-by-Environment Interaction in Grapevine Clones

Genotype-by-environment interaction (GEI) challenges selection in clonally propagated perennial crops by reducing the consistency of clone performance across years. In perennial crops, both genetic and epigenetic variation are likely to contribute to complex trait variation among clones. However, the extent to which each molecular source contribute to GEI remains poorly understood. Here, we used UMR-seq, an assay that recovers SNPs and unmethylated-region (UMR; DNA methylation) profiles from a single library, to generate paired genomic and epigenomic profiles for 206 Riesling (Vitis vinifera L.) clones phenotyped for yield and juice quality traits across nine growing seasons. We then partitioned the contribution of each omic layer to clonal variation and GEI, and examined the genomic distribution of their effects. In models without explicit GEI, environmental and residual effects were the largest source of phenotypic variance and the clonal main effect was modest. Genomic relationships accounted for most of the clonal variance in four of five traits, and adding an epigenomic relationship matrix (ERM) to the genomic relationship matrix (GRM) had little effect. In contrast, when GEI effects were modelled using factor-analytic covariance structures, the epigenomic layer captured a substantial proportion of GEI variance and exceeded the genomic contribution in four of five traits. The two omic layers differed not only in the amount of GEI captured, but also in the pattern of clone re-ranking across years. When back-solved effects were aggregated into genomic windows, the largest genomic and epigenomic effects tended to fall in different regions, with overlap no greater than expected by chance. Together, these results show that genomic and epigenomic relationships capture complementary components of year-to-year variation in clone performance, with the epigenomic contribution expressed primarily through GEI. These findings provide a basis for investigating the molecular drivers of GEI and for testing whether genomic and epigenomic information can inform selection for stable clonal performance across variable environments.

genetics↗