Huntington’s disease-specific mis-splicing captured by human-mouse intersect-RNA-seq unveils pathogenic effectors and reduced splicing factors

Elorza, Ainara; Márquez, Yamile; Cabrera, Jorge Rubén; Sanchez-Trincado, Jose L.; Santos-Galindo, María; Hernández, Ivó H.; Díaz‐Hernandéz, Juan Ignacio; García‐Escudero, Ramón; Irimia, Manuel; Lucas, José J.

doi:10.1101/2020.05.11.086017

Cited by 6 publications

(7 citation statements)

References 42 publications

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“…brain, muscle), usually through the action of tissue-enriched alternative splicing factors, and are known to play crucial roles in cellular differentiation and physiology [33, 34]. Moreover, some sets of exons have been shown to be jointly mis-regulated in human pathologies, including cancer or mental disorders [35, 36], and the evolutionary comparison between human and model organisms is a powerful approach to identify potential pathogenic targets [37]. The ExOrthist compare_exon_sets module allows the evaluation of the evolutionary conservation of exon sets between two species from a genomic and regulatory perspective, both at the gene and exon level (Fig.…”

Section: Resultsmentioning

confidence: 99%

ExOrthist: a tool to infer exon orthologies at any evolutionary distance

Márquez

Mantica

Cozzuto

et al. 2021

Preprint

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Several bioinformatic tools have been developed for genome-wide identification of orthologous and paralogous genes among species. However, no existing tool allows the detection of orthologous/paralogous exons. Here, we present ExOrthist, a fully reproducible Nextflow-based software enabling to (i) infer exon homologs and orthogroups, (ii) visualize evolution of exon-intron structures, and (iii) assess conservation of alternative splicing patterns. ExOrthist not only evaluates exon sequence conservation but also considers the surrounding exon-intron context to derive genome-wide multi-species exon homologies at any evolutionary distance. We demonstrate its use in various evolutionary scenarios, from whole genome duplication to convergence of alternative splicing networks.

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Section: Resultsmentioning

confidence: 99%

ExOrthist: a tool to infer exon orthologies at any evolutionary distance

Márquez

Mantica

Cozzuto

et al. 2021

Preprint

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“…Since P2X7R protein levels are augmented in HD striatum, we investigated whether this increase is associated with a higher amount of total P2X7R transcript in this brain area. To achieve such aim, we analyzed an RNA-seq study of the striatum of HD patients and controls that we have recently performed ( Elorza et al, 2020 ). We found a strong increase in total P2X7R transcript level (2.4-fold, q = 0.005) in HD subjects ( Figure 3A ).…”

Section: Resultsmentioning

confidence: 99%

“…P2X7R expression levels in HD and CTRL postmortem striatum samples were evaluated from our RNA-seq data (CTRL = 3 vs. HD = 3) ( Elorza et al, 2020 ). For total mRNA transcript levels, reads were aligned against the Homo sapiens genome (GRCh38.p2 version) using the TopHat2 aligner ( Trapnell et al, 2009 ), and differentially expressed genes were obtained with the Cuffdiff software ( Trapnell et al, 2013 ).…”

Section: Methodsmentioning

confidence: 99%

P2X7 Receptor Upregulation in Huntington’s Disease Brains

Ollá

Santos-Galindo

Elorza

et al. 2020

Front. Mol. Neurosci.

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Huntington’s disease (HD) is a fatal degenerative disorder affecting the nervous system. It is characterized by motor, cognitive, and psychiatric dysfunctions, with a late onset and an autosomal dominant pattern of inheritance. HD-causing mutation consists in an expansion of repeated CAG triplets in the huntingtin gene ( HTT ), encoding for an expanded polyglutamine (polyQ) stretch in the huntingtin protein (htt). The mutation causes neuronal dysfunction and loss through multiple mechanisms, affecting both the nucleus and cytoplasm. P2X7 receptor (P2X7R) emerged as a major player in neuroinflammation, since ATP – its endogenous ligand – is massively released under this condition. Indeed, P2X7R stimulation in the central nervous system (CNS) is known to enhance the release of pro-inflammatory cytokines from microglia and of neurotransmitters from neuronal presynaptic terminals, as well as to promote apoptosis. Previous experiments performed with neurons expressing the mutant huntingtin and exploiting HD mouse models demonstrated a role of P2X7R in HD. On the basis of those results, here, we explore for the first time the status of P2X7R in HD patients’ brain. We report that in HD postmortem striatum, as earlier observed in HD mice, the protein levels of the full-length form of P2X7R, also named P2X7R-A, are upregulated. In addition, the exclusively human naturally occurring variant lacking the C-terminus region, P2X7R-B, is upregulated as well. As we show here, this augmented protein levels can be explained by elevated mRNA levels. Furthermore, in HD patients’ striatum, P2X7R shows not only an augmented total transcript level but also an alteration of its splicing. Remarkably, P2X7R introns 10 and 11 are more retained in HD patients when compared with controls. Taken together, our data confirm that P2X7R is altered in brains of HD subjects and strengthen the notion that P2X7R may represent a potential therapeutic target for HD.

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“…Additionally, in a recent study, Elorza et al performed intersect-RNA-seq analyses of human postmortem striatal tissue and of an early symptomatic mouse model in which neuronal loss and gliosis were not yet present. This, in combination with a human–mouse parallel motif scan analysis, allowed for the identification of a shared mis-splicing signature that was triggered by the CAG-repeat mutation in both species and gives rise to a total of 949 one-to-one orthologs that are differentially spliced in both human and mouse [ 61 ]. In addition, via human–mouse parallel complementary motif searches on common mis-spliced events, the authors concluded a network of candidate upstream splicing factors with reduced protein levels in both species that may be mechanistically involved in mis-splicing [ 61 ].…”

Section: Deregulated Splicingmentioning

confidence: 99%

“…This, in combination with a human–mouse parallel motif scan analysis, allowed for the identification of a shared mis-splicing signature that was triggered by the CAG-repeat mutation in both species and gives rise to a total of 949 one-to-one orthologs that are differentially spliced in both human and mouse [ 61 ]. In addition, via human–mouse parallel complementary motif searches on common mis-spliced events, the authors concluded a network of candidate upstream splicing factors with reduced protein levels in both species that may be mechanistically involved in mis-splicing [ 61 ]. Interestingly, some of these splicing factors, for example, U2AF2 and HNRNPC, were previously found to aberrantly bind to CAG-repeat RNA [ 52 ].…”

Section: Deregulated Splicingmentioning

confidence: 99%

Huntingtin and Its Role in Mechanisms of RNA-Mediated Toxicity

Heinz

Nabariya

Krauß

2021

Toxins

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Huntington’s disease (HD) is caused by a CAG-repeat expansion mutation in the Huntingtin (HTT) gene. It is characterized by progressive psychiatric and neurological symptoms in combination with a progressive movement disorder. Despite the ubiquitous expression of HTT, pathological changes occur quite selectively in the central nervous system. Since the discovery of HD more than 150 years ago, a lot of research on molecular mechanisms contributing to neurotoxicity has remained the focal point. While traditionally, the protein encoded by the HTT gene remained the cynosure for researchers and was extensively reviewed elsewhere, several studies in the last few years clearly indicated the contribution of the mutant RNA transcript to cellular dysfunction as well. In this review, we outline recent studies on RNA-mediated molecular mechanisms that are linked to cellular dysfunction in HD models. These mechanisms include mis-splicing, aberrant translation, deregulation of the miRNA machinery, deregulated RNA transport and abnormal regulation of mitochondrial RNA. Furthermore, we summarize recent therapeutical approaches targeting the mutant HTT transcript. While currently available treatments are of a palliative nature only and do not halt the disease progression, recent clinical studies provide hope that these novel RNA-targeting strategies will lead to better therapeutic approaches.

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Huntington’s disease-specific mis-splicing captured by human-mouse intersect-RNA-seq unveils pathogenic effectors and reduced splicing factors

Cited by 6 publications

References 42 publications

ExOrthist: a tool to infer exon orthologies at any evolutionary distance

ExOrthist: a tool to infer exon orthologies at any evolutionary distance

P2X7 Receptor Upregulation in Huntington’s Disease Brains

Huntingtin and Its Role in Mechanisms of RNA-Mediated Toxicity

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