Open chromatin structure in PolyQ disease-related genes: a potential mechanism for CAG repeat expansion in the normal human population

Sorek, Matan; Cohen, Lea R Z; Meshorer, Eran

doi:10.1093/nargab/lqz003

Cited by 10 publications

(12 citation statements)

References 36 publications

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“…For example, decreased nucleosome occupancy likely promotes large-scale GAA repeat expansion in yeast (367). Consistently, bioinformatic analysis revealed that, in human cells, expandable CAG repeats are located in open chromatin regions, unlike stable CAG repeats (471).…”

Section: Role Of the Chromatin Environment In Repeat Instabilitymentioning

confidence: 72%

“…Several pieces of evidence support this idea. First, tandem repeat loci (but not the lengths of the repeats) are conserved in related species (471,485). At least some of these repeats seem to be actively maintained (486), which indicates that the existence of tandem repeats in these loci could be advantageous from an evolutionarystandpoint.Sometimes,tandemrepeatsitesevenevolveindependently in homologous genes (132).…”

Section: What Could Be the Advantages Of Having So Many Tandem Repeatmentioning

confidence: 99%

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On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Khristich

Mirkin

2020

Journal of Biological Chemistry

232

239

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Expansions of simple tandem repeats are responsible for almost 50 human diseases, the majority of which are severe, degenerative, and not currently treatable or preventable. In this review, we first describe the molecular mechanisms of repeat-induced toxicity, which is the connecting link between repeat expansions and pathology. We then survey alternative DNA structures that are formed by expandable repeats and review the evidence that formation of these structures is at the core of repeat instability. Next, we describe the consequences of the presence of long structure-forming repeats at the molecular level: somatic and intergenerational instability, fragility, and repeat-induced mutagenesis. We discuss the reasons for gender bias in intergenerational repeat instability and the tissue specificity of somatic repeat instability. We also review the known pathways in which DNA replication, transcription, DNA repair, and chromatin state interact and thereby promote repeat instability. We then discuss possible reasons for the persistence of disease-causing DNA repeats in the genome. We describe evidence suggesting that these repeats are a payoff for the advantages of having abundant simple-sequence repeats for eukaryotic genome function and evolvability. Finally, we discuss two unresolved fundamental questions: (i) why does repeat behavior differ between model systems and human pedigrees, and (ii) can we use current knowledge on repeat instability mechanisms to cure repeat expansion diseases?

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Section: Role Of the Chromatin Environment In Repeat Instabilitymentioning

confidence: 72%

Section: What Could Be the Advantages Of Having So Many Tandem Repeatmentioning

confidence: 99%

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Khristich

Mirkin

2020

Journal of Biological Chemistry

232

239

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“…To this end, we used a large-scale dataset including multiple ChIP-seq profiles for transcription factors (TFs) and histone modifications (HMs) in A549 cells (Schreiber et al, 2020). Since for A549 cells we also have pre- and post-SARS-CoV-2 infection data, it allowed us to examine the ‘epigenetic signature’ (Sorek et al, 2019) (relative enrichment of TFs and HMs) around the TEs that are up-regulated post-infection of SARS-CoV-2 and IAV (Figure 3 and S3).…”

Section: Resultsmentioning

confidence: 99%

Impaired activation of Transposable Elements in SARS-CoV-2 infection

Sorek

Meshorer

Schlesinger

2021

Preprint

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Transposable elements (TEs) are induced in response to viral infections. TEs induction triggers a robust and durable interferon (IFN) response, providing a host defense mechanism. Still, the connection between SARS-CoV-2 IFN response and TEs remained unexplored. Here, we analyzed TE expression changes in response to SARS-CoV-2 infection in different human cellular models. We find that compared to other viruses, which cause global upregulation of TEs, SARS-CoV-2 infection results in a significantly milder TE response in both primary lung epithelial cells and in iPSC-derived lung alveolar type 2 cells. In general, we observe that TE activation correlates with, and precedes, the induction of IFN-related genes, suggesting that the failure to activate TEs may be the reason for the weak IFN response. Moreover, we identify two variables which explain most of the observed diverseness in immune responses: basal expression levels of TEs in the pre-infected cell, and the viral load. Since basal TE levels increase with age, we propose that "TE desensitization" leads to age-related death from COVID19. This work provides a potential mechanistic explanation for SARS-CoV-2s success in its fight against the host immune system, and suggests that TEs could be used as sensors or serve as potential drug targets for COVID-19.

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“…This reflects a common feature for polyQ disease-related genes that share a very active profile enriched in active marks and depleted in repressive marks in unaffected individuals. It has been suggested that an open chromatin state could be the cause of genomic instability, and in this sense, the heterochromatinization process can be considered as a protective mechanism from acquiring more mutations [56]. Finally, recent studies revealed a link between 3D genome folding and several expansion disorders in which genes are placed at the boundaries between topologically associating domains (TADs) that are highly enriched on CpG islands, suggesting that repeat expansions could disrupt TADs structure, resulting in a reorganization of the genome topology [57].…”

Section: Chromatin Remodeling Of Dm1 Locusmentioning

confidence: 99%

Epigenetics of Myotonic Dystrophies: A Minireview

Visconti

Centofanti

Fittipaldi

et al. 2021

IJMS

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Myotonic dystrophy type 1 and 2 (DM1 and DM2) are two multisystemic autosomal dominant disorders with clinical and genetic similarities. The prevailing paradigm for DMs is that they are mediated by an in trans toxic RNA mechanism, triggered by untranslated CTG and CCTG repeat expansions in the DMPK and CNBP genes for DM1 and DM2, respectively. Nevertheless, increasing evidences suggest that epigenetics can also play a role in the pathogenesis of both diseases. In this review, we discuss the available information on epigenetic mechanisms that could contribute to the DMs outcome and progression. Changes in DNA cytosine methylation, chromatin remodeling and expression of regulatory noncoding RNAs are described, with the intent of depicting an epigenetic signature of DMs. Epigenetic biomarkers have a strong potential for clinical application since they could be used as targets for therapeutic interventions avoiding changes in DNA sequences. Moreover, understanding their clinical significance may serve as a diagnostic indicator in genetic counselling in order to improve genotype–phenotype correlations in DM patients.

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Open chromatin structure in PolyQ disease-related genes: a potential mechanism for CAG repeat expansion in the normal human population

Cited by 10 publications

References 36 publications

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

Impaired activation of Transposable Elements in SARS-CoV-2 infection

Epigenetics of Myotonic Dystrophies: A Minireview

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