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

Abstract

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.

The Effect of Glucocorticoids on TAF1 Gene Transcription in X-linked Dystonia Parkinsonism

“…In promoter-luciferase assays, the XDP-SVA has been shown to exhibit intrinsic promoter activity 6 as well as cis-regulatory activity via TAF1 promoter repression. 7 It has been proposed that the insertion of the SVA retrotransposon provides new binding sites within the locus, which may lead to the transcriptional interference of TAF1 or the binding of trans-acting elements that contribute to disease progression. 6 Several studies have also looked into the psychosocial aspect of XDP.…”

Neuroenergetic Changes in Patients with X‐Linked Dystonia‐Parkinsonism and Female Carriers

“…Although the genetic underpinnings of XDP are increasingly understood, the broader molecular consequences of this insertion remain widely elusive. 2,8,9 The in vivo evaluation of potentially involved molecular pathways could provide insights into potential therapeutic targets for XDP. One unifying concept in the development and progression of several neurodegenerative diseases is bioenergetic changes because of mitochondrial dysfunction.…”

“…These cerebellar changes, although less explored than the degeneration of the basal ganglia, might play a role in the progression and symptomatology in XDP. Although the genetic underpinnings of XDP are increasingly understood, the broader molecular consequences of this insertion remain widely elusive 2,8,9 . The in vivo evaluation of potentially involved molecular pathways could provide insights into potential therapeutic targets for XDP.…”

Transcriptional Regulation and Its Misregulation in Human Diseases

“…In this Special Issue, a total of 18 excellent and interesting papers [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20], consisting of 13 original research studies [3][4][5][6][10][11][12][14][15][16][18][19][20], as well as five reviews, are published [7][8][9]13,17]. They cover many subjects of transcriptional regulation, including studies on cis-regulatory elements, transcription factors (TF), chromatin regulators, and ncRNAs.…”

“…However, it is increasingly evident that, under the influence of genetic and epigenetic mechanisms, they can be involved in some physiological and pathological conditions; examples are their function in embryonic development, or, even more importantly, their reactivation in the development of human diseases, such as cancer and neurodegenerative disorders [13]. Besides, a remarkable paper [14] shows that transcriptional alterations observed in X-linked dystonia-parkinsonism (XDP) are caused by the insertion of a SINE-VNTR-Alu (SVA) retrotransposon in an intron of the TAF1 (TATA-Box Binding Protein Associated Factor 1) gene, encoding for the largest subunit of TFIID; as an interesting effect, increased levels of the TAF1 intron retention transcript TAF1-32i can be found in XDP cells, as compared to healthy controls. Overall, the results of this study provide further evidence that transposable elements affect gene expression and suggest that a mechanism of splicing alteration occurs in XDP patients, probably caused by binding sites for transcription factors and splicing regulators present within this retrotransposon and that need to be exactly proved through additional experiments [14].…”