Transcriptome alterations in myotonic dystrophy frontal cortex

Otero, Brittney A.; Poukalov, Kiril; Hildebrandt, Ryan P.; Thornton, Charles A.; Jinnai, Kenji; Fujimura, Harutoshi; Kimura, Takashi; Hagerman, Katharine A.; Sampson, Jacinda B.; Day, John W.; Wang, Eric T.

doi:10.1016/j.celrep.2020.108634

Cited by 46 publications

(85 citation statements)

References 67 publications

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“…Second, in line with the hypothesis of CUG RNA toxicity, molecular abnormalities were more pronounced in DMSXL astrocytes, which express the highest levels of DMPK transcripts, relative to other brain cell types. Third, there is significant overlapping between splicing changes in DMSXL mouse brain cells and those reported in human DM1 frontal cortex (Goodwin et al, 2015;Otero et al, 2021; Supplementary File 2). Fourth, Fbxl7 knock-out mice have not shown overt neurological phenotypes 5 .…”

Section: Discussionmentioning

confidence: 88%

“…Interestingly, and similar to the variations in gene expression, the number of cassette exons differentially spliced between DMSXL and WT cells increased from eight in OPC to 65 in OL primary cultures. In an attempt to gain insight into the factors contributing to the more severe spliceopathy of DMSXL astrocytes and OL, we quantified the levels of human DMPK transcripts, relative to mouse Mbnl1 and Mbnl2 , as previously described ( Otero et al, 2021 ). DMSXL astrocytes displayed the highest DMPK/Mbnl1 and DMPK/Mbnl2 ratios, followed by DMSXL oligodendrocytes ( Figure 5C ).…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, a substantial number of changes was detected in DMSXL OL. Our top downregulated gene in DMSXL OL ( Anxa6 ) has been recently found downregulated in DM1 frontal cortex, and proposed as a candidate CSF marker to study disease progression ( Otero et al, 2021 ). An additional six genes downregulated in DMSXL OL were also described to be differentially expressed in DM1 frontal cortex.…”

Section: Discussionmentioning

confidence: 98%

“…The high number of exons differentially spliced in DMSXL astrocytes prompted us to perform an exon ontology analysis (Otero et al, 2021). e PSI reported in DM1 human frontal cortex, relative to non-affected individuals (Goodwin et al, 2015).…”

Section: Exon Ontology and Functional Implications Of Splicing Changesmentioning

confidence: 99%

“…Still, the molecular and cellular mechanisms driving DM1 neurological impairment remain largely unknown. Previous studies analyzed the transcriptome of DM1 patients to uncover disease-related alterations ( Batra et al, 2014 ; Goodwin et al, 2015 ; Otero et al, 2021 ). While many of the events found are specific to the CNS, an inherent limitation of studying tissue samples is the lack of cell type resolution.…”

Section: Introductionmentioning

confidence: 99%

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Integrative Cell Type-Specific Multi-Omics Approaches Reveal Impaired Programs of Glial Cell Differentiation in Mouse Culture Models of DM1

González-Barriga

Lallemant

Dincã

et al. 2021

Front. Cell. Neurosci.

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Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a non-coding CTG repeat expansion in the DMPK gene. This mutation generates a toxic CUG RNA that interferes with the RNA processing of target genes in multiple tissues. Despite debilitating neurological impairment, the pathophysiological cascade of molecular and cellular events in the central nervous system (CNS) has been less extensively characterized than the molecular pathogenesis of muscle/cardiac dysfunction. Particularly, the contribution of different cell types to DM1 brain disease is not clearly understood. We first used transcriptomics to compare the impact of expanded CUG RNA on the transcriptome of primary neurons, astrocytes and oligodendrocytes derived from DMSXL mice, a transgenic model of DM1. RNA sequencing revealed more frequent expression and splicing changes in glia than neuronal cells. In particular, primary DMSXL oligodendrocytes showed the highest number of transcripts differentially expressed, while DMSXL astrocytes displayed the most severe splicing dysregulation. Interestingly, the expression and splicing defects of DMSXL glia recreated molecular signatures suggestive of impaired cell differentiation: while DMSXL oligodendrocytes failed to upregulate a subset of genes that are naturally activated during the oligodendroglia differentiation, a significant proportion of missplicing events in DMSXL oligodendrocytes and astrocytes increased the expression of RNA isoforms typical of precursor cell stages. Together these data suggest that expanded CUG RNA in glial cells affects preferentially differentiation-regulated molecular events. This hypothesis was corroborated by gene ontology (GO) analyses, which revealed an enrichment for biological processes and cellular components with critical roles during cell differentiation. Finally, we combined exon ontology with phosphoproteomics and cell imaging to explore the functional impact of CUG-associated spliceopathy on downstream protein metabolism. Changes in phosphorylation, protein isoform expression and intracellular localization in DMSXL astrocytes demonstrate the far-reaching impact of the DM1 repeat expansion on cell metabolism. Our multi-omics approaches provide insight into the mechanisms of CUG RNA toxicity in the CNS with cell type resolution, and support the priority for future research on non-neuronal mechanisms and proteomic changes in DM1 brain disease.

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Section: Discussionmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 98%

Section: Exon Ontology and Functional Implications Of Splicing Changesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Integrative Cell Type-Specific Multi-Omics Approaches Reveal Impaired Programs of Glial Cell Differentiation in Mouse Culture Models of DM1

González-Barriga

Lallemant

Dincã

et al. 2021

Front. Cell. Neurosci.

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Optical Genome Mapping for Applications in Repeat Expansion Disorders

van der Sanden,

Neveling,

Pang

et al. 2024

Current Protocols

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Short tandem repeat (STR) expansions are associated with more than 60 genetic disorders. The size and stability of these expansions correlate with the severity and age of onset of the disease. Therefore, being able to accurately detect the absolute length of STRs is important. Current diagnostic assays include laborious lab experiments, including repeat‐primed PCR and Southern blotting, that still cannot precisely determine the exact length of very long repeat expansions. Optical genome mapping (OGM) is a cost‐effective and easy‐to‐use alternative to traditional cytogenetic techniques and allows the comprehensive detection of chromosomal aberrations and structural variants >500 bp in length, including insertions, deletions, duplications, inversions, translocations, and copy number variants. Here, we provide methodological guidance for preparing samples and performing OGM as well as running the analysis pipelines and using the specific repeat expansion workflows to determine the exact repeat length of repeat expansions expanded beyond 500 bp. Together these protocols provide all details needed to analyze the length and stability of any repeat expansion with an expected repeat size difference from the expected wild‐type allele of >500 bp. © 2024 The Authors. Current Protocols published by Wiley Periodicals LLC.Basic Protocol 1: Genomic ultra‐high‐molecular‐weight DNA isolation, labeling, and stainingBasic Protocol 2: Data generation and genome mapping using the Bionano Saphyr® SystemBasic Protocol 3: Manual De Novo Assembly workflowBasic Protocol 4: Local guided assembly workflowBasic Protocol 5: EnFocus Fragile X workflowBasic Protocol 6: Molecule distance script workflow

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Myotonic Dystrophies

Silvestri,

Modoni

2023

Current Clinical Neurology

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Transcriptome alterations in myotonic dystrophy frontal cortex

Cited by 46 publications

References 67 publications

Integrative Cell Type-Specific Multi-Omics Approaches Reveal Impaired Programs of Glial Cell Differentiation in Mouse Culture Models of DM1

Integrative Cell Type-Specific Multi-Omics Approaches Reveal Impaired Programs of Glial Cell Differentiation in Mouse Culture Models of DM1

Optical Genome Mapping for Applications in Repeat Expansion Disorders

Myotonic Dystrophies

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