Accelerated epigenetic aging in Huntington’s disease involves polycomb repressive complex 1

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 11, 2025

Abstract Loss of epigenetic information during physiological aging compromises cellular identity, leading to de-repression developmental genes. Here, we assessed the epigenomic landscape vulnerable neurons in two reference mouse models Huntington neurodegenerative disease (HD), using cell-type-specific multi-omics, including temporal analysis at three stages via FANS-CUT&Tag. We show accelerated genes HD striatal neurons, involving histone re-acetylation and depletion H2AK119 ubiquitination H3K27 trimethylation marks, which are catalyzed by polycomb repressive complexes 1 2 (PRC1 PRC2), respectively. further identify a PRC1-dependent subcluster bivalent transcription factors that is re-activated neurons. This mechanism likely involves progressive paralog switching between PRC1-CBX genes, promotes upregulation normally low-expressed PRC1-CBX2/4/8 isoforms alongside down-regulation predominant these cells (e.g., CBX6/7). Collectively, our data provide evidence for

Language: Английский

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Revealed: Why the fatal Huntington’s gene takes so long to cause harm

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Language: Английский

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Huntington’s disease gene variants past a certain size poison select cells

The Transmitter, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Somatic CAG-repeat expansion drives neuronal loss in Huntington’s disease

Neuron, Journal Year: 2025, Volume and Issue: 113(3), P. 342 - 344

Published: Feb. 1, 2025

Language: Английский

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Mosaicism in Short Tandem Repeat Disorders: A Clinical Perspective

Genes, Journal Year: 2025, Volume and Issue: 16(2), P. 216 - 216

Published: Feb. 13, 2025

Fragile X, Huntington disease, and myotonic dystrophy type 1 are prototypical examples of human disorders caused by short tandem repeat variation, repetitive nucleotide stretches that highly mutable both in the germline somatic tissue. As repeats unstable, they can expand, contract, acquire lose epigenetic marks This means within an individual, genotype state at these loci vary considerably from cell to cell. mosaicism may play a key role clinical pathogenesis, yet, our understanding driving phenotypes is only just emerging. review focuses on three relatively well-studied where, given advent new technologies bioinformatic approaches, critical for coming into focus with respect cellular physiology phenotypes.

Language: Английский

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The breaking point where repeat expansion triggers neuronal collapse in Huntington’s disease

Cell Genomics, Journal Year: 2025, Volume and Issue: 5(3), P. 100816 - 100816

Published: March 1, 2025

Somatic CAG expansion drives neuronal loss in Huntington's disease (HD), but how results pathogenesis has remained unclear. Handsaker et al.1 use single-cell RNA and repeat length sequencing to reveal a phased model of toxicity, highlighting critical tipping point beyond 150 repeats where identity collapses cells die.

Language: Английский

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ONT in Clinical Diagnostics of Repeat Expansion Disorders: Detection and Reporting Challenges

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(6), P. 2725 - 2725

Published: March 18, 2025

While whole-genome sequencing (WGS) using short-read technology has become a standard diagnostic test, this limitations in analyzing certain genomic regions, particularly short tandem repeats (STRs). These repetitive sequences are associated with over 50 diseases, primarily affecting neurological function, including Huntington disease, frontotemporal dementia, and Friedreich’s ataxia. We analyzed 2689 cases movement disorders dementia-related phenotypes processed at Variantyx 2023–2024 two-tiered approach, an initial WGS followed by ONT long-read (when necessary) for variant characterization. Of the 2038 (75.8%) clinically relevant genetic variants, 327 (16.0%) required additional analysis. STR variants were reported 338 (16.6% of positive cases), approximately half requiring definitive classification. The combined approach enabled precise determination repeat length, composition, somatic mosaicism, methylation status. Notable advantages included detection complex structures several genes such as RFC1, FGF14, FXN, where allowed to determine unit variations accurate allele phasing. Further studies needed establish technology-specific guidelines standardized interpretation data clinical diagnostics expansion disorders.

Language: Английский

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Errors in the Huntington’s disease gene accumulate slowly and then all at once

Nature, Journal Year: 2025, Volume and Issue: 639(8055), P. 584 - 586

Published: March 17, 2025

Language: Английский

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Uncontrolled CAG expansion in neurons susceptible to Huntington's disease

The Lancet Neurology, Journal Year: 2025, Volume and Issue: 24(4), P. 282 - 284

Published: March 20, 2025

Language: Английский

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Single-cell genomics technologies and cell atlases have ushered in a new era of human neurobiology

The Transmitter, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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