LINE-1 activation in the cerebellum drives ataxia

Takahashi, Takehiro; Kudo, Eriko; Song, Eric; Carvalho, F.; Yasumoto, Yuki; Kong, Yong; Park, Annsea; Stoiljković, Milan; Gao, Xiao-Bing; Shanabrough, Marya; Szigeti‐Buck, Klara; Liu, Zhongwu; Zhang, Yalan; Sulkowski, Parker L.; Glazer, Peter M.; Kaczmarek, Leonard K.; Horváth, Tamas L.; Iwasaki, Akiko

doi:10.1101/2021.12.03.471151

Cited by 3 publications

(6 citation statements)

References 49 publications

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“…This finding is of interest in 21 highlighting the potential role of LINE/L1 dysregulation in pathogenesis, as found by a recent RNA-sequencing study that demonstrated cerebellar LINE/L1 activation in driving ataxia phenotype in mouse models. 54 Our analyses highlighted not only the potential for common pathogenic mechanisms for disease across hereditary ataxia, but also common biology. Intriguingly, we found no clear separation of genes causing childhood-and adult-onset ataxia using UMAP to visualise genes based on a recursively-selected set of features.…”

Section: Discussionmentioning

confidence: 87%

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Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia

Chen

Tucci

Cipriani

et al. 2022

Preprint

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Improvements in functional genomic annotation have led to a critical mass of neurogenetic discoveries. This is exemplified in hereditary ataxia, a heterogeneous group of disorders characterised by incoordination from cerebellar dysfunction. Associated pathogenic variants in more than 300 genes have been described, leading to a detailed genetic classification partitioned by age-of-onset. Despite these advances, up to 75% of patients with ataxia remain molecularly undiagnosed even following whole genome sequencing, as exemplified in the 100,000 Genomes Project. This study aimed to understand whether we can improve our knowledge of the genetic architecture of hereditary ataxia by leveraging functional genomic annotations, and as a result, generate insights that raise the diagnostic yield. To achieve these aims, we used publicly-available multi-omics data to generate 294 genic features, capturing information relating to a gene's structure, genetic variation, tissue-specific, cell-type-specific and temporal expression, as well as protein products of a gene. We studied these features across genes typically causing childhood-onset, adult-onset or both types of disease first individually, then collectively. This led to the generation of testable hypotheses which we investigated using whole genome sequencing data from 2,322 individuals presenting with ataxia and 6,387 non-neurological probands in the 100,000 Genomes Project. Using this approach, we demonstrated a surprisingly high short tandem repeat (STR) density within childhood-onset genes suggesting that we may be missing pathogenic repeat expansions within this cohort. This was verified in both childhood- and adult-onset ataxia patients from the 100,000 Genomes Project who were unexpectedly found to have a trend for higher repeat sizes even at naturally-occurring STRs in known ataxia genes, implying a role for STRs in pathogenesis. Using unsupervised analysis, we found significant similarities in genomic annotation across the gene panels, which suggested adult- and childhood-onset patients should be screened using a common diagnostic gene set. We tested this within the 100,000 Genomes Project by assessing the burden of pathogenic variants among childhood-onset genes in adult-onset patients and vice versa. This demonstrated a significantly higher burden of rare, potentially pathogenic variants in conventional childhood-onset genes among individuals with adult-onset ataxia. Our analysis has implications for the current clinical practice in genetic testing for hereditary ataxia. We suggest that the diagnostic rate for hereditary ataxia could be increased by removing the age-of-onset partition, and through a modified screening for repeat expansions in naturally-occurring STRs within known genes, in effect treating these regions as candidate pathogenic loci.

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Section: Discussionmentioning

confidence: 87%

“…This finding is of interest in highlighting the potential role of LINE/L1 dysregulation in pathogenesis, as found by a recent RNA-sequencing study that demonstrated cerebellar LINE/L1 activation in driving ataxia phenotype in mouse models. 54…”

Section: Discussionmentioning

confidence: 99%

Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia

Chen

Tucci

Cipriani

et al. 2022

Preprint

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“…The deregulation of REs is closely linked with human diseases, in particular neurodevelopmental disorders. For instance, ERV dys-regulation in the brain is thought to cause several neurodevelopmental and neurodegenerative disorders (NDDs) such as schizophrenia and amyotrophic lateral sclerosis (Douville et al 2011), and LINE-1 activation drives ataxia (Takahashi et al, 2022). Of note, recent studies have emphasized the importance of differential splicing and isoform-level gene regulatory mechanisms in defining cell type and neural disease specificity (Gandal et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…However, the upstream regulators and how TRIM28 and SETDB1 are targeted to specific REs remain elusive. Of note, aberrant RE activation in somatic cells is closely linked with various diseases, including neural disorders (Douville et al 2011; Payer and Burns, 2019; Takahashi et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

POGZ suppresses 2C transcriptional program and retrotransposable elements

Sun

Zhang

Cheng

et al. 2022

Preprint

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ThePOGZgene has been found frequently mutated in neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and intellectual disability (ID). We have recently shown that POGZ maintains mouse embryonic stem cells (ESCs) as a chromatin regulator and a transcription factor. However, the exact mechanisms remain unclear. Here we show that POGZ plays important role in the maintenance of ESCs by silencing theDuxgene and certain endogenous retroviruses (ERVs). POGZ directly binds to theDuxgene and ERVs, and its depletion leads to up-regulation of 2C genes and the repetitive elements such as RLTR9E and IAP (the intracisternal A-type particles), resulting in transition to a 2C-like (2CLC) state and genome instability. POGZ regulates ESC heterochromatin state by association and recruiting TRIM28 and SETDB1, and its loss leads to increased H3K4me3 and H3K27ac, and decreased H3K9me3 at local chromatin. Activation of POGZ-bound ERVs is associated with up-regulation of nearby neural genes. Chimeric transcripts that are initiated within ERVs and spliced to genic exons are highly expressed inPogz−/−ESCs. Our findings establish that POGZ is required for the maintenance of ESCs by repressingDuxand silencing ERVs, which may provide important insights into the disease pathology caused by POGZ dysfunction.HighlightsPOGZ depletion leads to activation of 2C genesPOGZ depletion leads to deregulation of ERVsPOGZ directly binds and repressesDuxPOGZ associates with TRIM28/SETDB1 to maintain heterochromatin state to silence ERVsActivation of POGZ-bound ERVs is associated with up-regulation of nearby neural genes

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“…In recent work, Takahashi et al concluded that L1 can drive neurodegeneration in AT, based on increased cerebellar L1 RNA abundance in AT patients, as well as ataxia and neurodegeneration in mice where L1 transcription was activated in the cerebellum via a dCas9-CRISPR approach (Takahashi et al, 2022). This intriguing study could shape strategies to treat or prevent AT in children and, for this reason, its findings warrant careful consideration.…”

Section: Mainmentioning

confidence: 99%

Elevated L1 expression in ataxia telangiectasia likely explained by an RNA-seq batch effect

Faulkner

2022

Preprint

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A recent study (Takahashi et al., Neuron, 2022) concluded LINE-1 (L1) retrotransposon activation drives cerebellar ataxia and neurodegeneration. This position was based on L1 upregulation in ataxia telangiectasia (AT) patient cerebellum samples, as measured by RNA-seq, and observation of ataxia and neurodegeneration in mice where cerebellar L1 expression was induced via dCas9-CRISPR. Here, a re-analysis of the RNA-seq data, which were obtained by rRNA depletion rather than polyA+ selection, revealed a high fraction (38.4%) of intronic reads. Significantly (p=0.034) more intronic reads were present in the AT data than the matched controls. This finding provides an alternative and robust explanation for a key result reported by Takahashi et al.: intronic L1 sequences are abundant in pre-mRNAs, and more pre-mRNAs were retained in the AT libraries. This apparent batch effect deserves further examination, as claims of L1-mediated pathogenesis could shape future efforts to treat AT by trying to attenuate L1 activity.

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LINE-1 activation in the cerebellum drives ataxia

Cited by 3 publications

References 49 publications

Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia

Functional genomics provide key insights to improve the diagnostic yield of hereditary ataxia

POGZ suppresses 2C transcriptional program and retrotransposable elements

Elevated L1 expression in ataxia telangiectasia likely explained by an RNA-seq batch effect

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