SVA insertion in X-linked Dystonia Parkinsonism alters histone H3 acetylation associated with TAF1 gene

Petrozziello, Tiziana; Dios, Amanda M.; Mueller, Kaly A.; Vaine, Christine A.; Hendriks, William T.; Glajch, Kelly E.; Mills, Alexandra N.; Mangkalaphiban, Kotchaphorn; Penney, Ellen B.; Ito, Naoto; Fernandez-Cerado, Cara; Legarda, G. Paul; Velasco-Andrada, M. Salvie; Acuña, Patrick; Ang, Mark Angelo C.; Muñoz, Edwin L.; Diesta, Cid Czarina E.; Macalintal-Canlas, Regina; Acuña, Geraldine; Sharma, Nutan; Ozelius, Laurie J.; Bragg, D. Cristopher; Sadri‐Vakili, Ghazaleh

doi:10.1371/journal.pone.0243655

Cited by 11 publications

(10 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These elements are polymorphic in multiple domains, including the variable number tandem repeat (VNTRs) element and the CT hexamer repeat in one of the termini. The latter variation affects age of onset in XDP [42]. VNTRs more generally have been studied extensively as both biomarkers and functional elements in the context of complex genetics for many years, and these elements have been shown to have tissue-specific and stimulus-inducible regulatory properties, which are modified further by polymorphism in the VNTR itself [43].…”

Section: Discussionmentioning

confidence: 99%

Expression Quantitative Trait Loci (eQTLs) Associated with Retrotransposons Demonstrate their Modulatory Effect on the Transcriptome

Kõks

Pfaff

Bubb

et al. 2021

IJMS

View full text Add to dashboard Cite

Transposable elements (TEs) are repetitive elements that belong to a variety of functional classes and have an important role in shaping genome evolution. Around 50% of the human genome contains TEs, and they have been termed the “dark matter” of the genome because relatively little is known about their function. While TEs have been shown to participate in aberrant gene regulation and the pathogenesis of diseases, only a few studies have explored the systemic effect of TEs on gene expression. In the present study, we analysed whole genome sequences and blood whole transcriptome data from 570 individuals within the Parkinson’s Progressive Markers Initiative (PPMI) cohort to identify expression quantitative trait loci (eQTL) regulating genome-wide gene expression associated with TEs. We identified 2132 reference TEs that were polymorphic for their presence or absence in our study cohort. The presence or absence of the TE element could change the expression of the gene or gene clusters from zero to tens of thousands of copies of RNA. The main finding is that many TEs possess very strong regulatory effects, and they have the potential to modulate large genetic networks with hundreds of target genes over the genome. We illustrate the plethora of regulatory mechanisms using examples of their action at the HLA gene cluster and data showing different TEs' convergence to modulate WFS1 gene expression. In conclusion, the presence or absence of polymorphisms of TEs has an eminent genome-wide regulatory function with large effect size at the level of the whole transcriptome. The role of TEs in explaining, in part, the missing heritability for complex traits is convincing and should be considered.

show abstract

Section: Discussionmentioning

confidence: 99%

Expression Quantitative Trait Loci (eQTLs) Associated with Retrotransposons Demonstrate their Modulatory Effect on the Transcriptome

Kõks

Pfaff

Bubb

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…For instance, recent work on XDP-derived cells reported local changes in H3 acetylation (AcH3), affecting an exon proximal to the SVA insertion. This decrease in AcH3 level was normalized by CRISPR/Cas9-excision of the SVA, suggesting that the SVA alters epigenetic marks in the region [39]. In addition, a significant increase in histone H3 citrullination (H3R2R8R17cit3) was reported in the XDP post-mortem prefrontal cortex [40].…”

Section: Discussionmentioning

confidence: 93%

Transcriptional Alterations in X-Linked Dystonia–Parkinsonism Caused by the SVA Retrotransposon

Pozojevic

Algodon

Cruz

et al. 2022

IJMS

Self Cite

View full text Add to dashboard Cite

X-linked dystonia–parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA) retrotransposon inserted in an intron of the TAF1 gene reduces its expression and alters splicing in XDP patient-derived cells. As a consequence, increased levels of the TAF1 intron retention transcript TAF1-32i can be found in XDP cells as compared to healthy controls. Here, we investigate the sequence of the deep intronic region included in this transcript and show that it is also present in cells from healthy individuals, albeit in lower amounts than in XDP cells, and that it undergoes degradation by nonsense-mediated mRNA decay. Furthermore, we investigate epigenetic marks (e.g., DNA methylation and histone modifications) present in this intronic region and the spanning sequence. Finally, we show that the SVA evinces regulatory potential, as demonstrated by its ability to repress the TAF1 promoter in vitro. Our results enable a better understanding of the disease mechanisms underlying XDP and transcriptional alterations caused by SVA retrotransposons.

show abstract

“…Our understanding of XDP's causal factors had been limited to prior discoveries highlighting variable expression of TAF1 isoforms (2,3,54,74), the pathogenic effect of SVA insertion (5,75), or DNA repair genes (67). However, our study has now validated the presence of additional genes that differ in XDP-MSNs and can be modulated by SAK3 that protects XDP-MSNs from neurodegeneration.…”

Section: Discussionmentioning

confidence: 99%

SAK3 confers neuroprotection in the neurodegeneration model of X-linked Dystonia-Parkinsonism

Aryal,

Chen,

Burbach

et al. 2024

Preprint

View full text Add to dashboard Cite

Background X-linked Dystonia-Parkinsonism(XDP) is an adult-onset neurodegenerative disorder that results in the loss of striatal medium spiny neurons (MSNs). XDP is associated with disease-specific mutations in and around the TAF1 gene. This study highlights the utility of directly reprogrammed MSNs from fibroblasts of affected XDP individuals as a platform that captures cellular and epigenetic phenotypes associated with XDP-related neurodegeneration. In addition, the current study demonstrates the neuroprotective effect of SAK3 currently tested in other neurodegenerative diseases. Methods XDP fibroblasts from three independent patients as well as age- and sex-matched control fibroblasts were used to generate MSNs by direct neuronal reprogramming using miRNA-9/9*-124 and thetranscription factors CTIP2, DLX1-P2A-DLX2, and MYT1L. Neuronal death, DNA damage, and mitochondrial health assays were carried out to assess the neurodegenerative state of directly reprogrammed MSNs from XDP patients (XDP-MSNs). RNA sequencing and ATAC sequencing were performed to infer changes in the transcriptomic and chromatin landscapesof XDP-MSNs compared to those of control MSNs (Ctrl-MSNs). Results Our results show that XDP patient fibroblasts can be successfully reprogrammed into MSNs and XDP-MSNs display several degenerative phenotypes, including neuronal death, DNA damage, and mitochondrial dysfunction, compared to Ctrl-MSNs reprogrammed from age- and sex-matched control individuals’ fibroblasts. In addition, XDP-MSNs showed increased vulnerability to TNFα -toxicity compared to Ctrl-MSNs. To dissect the altered cellular state in XDP-MSNs, we conducted transcriptomic and chromatin accessibility analyses using RNA- and ATAC-seq. Our results indicate that pathways related to neuronal function, calcium signaling, and genes related to other neurodegenerative diseases are commonly altered in XDP-MSNs from multiple patients. Interestingly, we found that SAK3, a T-type calcium channel activator, that may have therapeutic values in other neurodegenerative disorders, protected XDP-MSNs from neuronal death. Notably, we found that SAK3-mediated alleviation of neurodegeneration in XDP-MSNs was accompanied by gene expression changes toward Ctrl-MSNs.

show abstract

SVA insertion in X-linked Dystonia Parkinsonism alters histone H3 acetylation associated with TAF1 gene

Cited by 11 publications

References 74 publications

Expression Quantitative Trait Loci (eQTLs) Associated with Retrotransposons Demonstrate their Modulatory Effect on the Transcriptome

Expression Quantitative Trait Loci (eQTLs) Associated with Retrotransposons Demonstrate their Modulatory Effect on the Transcriptome

Transcriptional Alterations in X-Linked Dystonia–Parkinsonism Caused by the SVA Retrotransposon

SAK3 confers neuroprotection in the neurodegeneration model of X-linked Dystonia-Parkinsonism

Contact Info

Product

Resources

About