Structural Variation at a Disease Mutation Hotspot: Strategies to Investigate Gene Regulation and the 3D Genome

Boyling, Alexandra; Perez-Siles, Gonzalo; Kennerson, Marina

doi:10.3389/fgene.2022.842860

Cited by 9 publications

(8 citation statements)

References 121 publications

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“…First, this aberrant same-sense transcription was seen only in GFP + cells (Fig 4C, D); second, the transcription correlated with the level of plus-strand proviral transcription in timer protein reporter clones (S8 Fig) . An unexpected finding in this study was that aberrant loop formation between the provirus and host chromatin is suppressed by proviral plus-strand transcription. Since CTCF appears to remain bound to the provirus during expression of tax [8], the observed decrease in Chromatin looping between the HTLV-1 provirus and the host genome is mediated by CTCF binding to the provirus [14]. We postulated that CTCF binding confers a selective advantage on the provirus; however, the mechanism of this putative advantage is not known.…”

Section: Discussionmentioning

confidence: 97%

The impact of HTLV-1 expression on the 3D structure and expression of host chromatin

Yaguchi,

Melamed,

Ramanayake

et al. 2023

Preprint

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A typical HTLV-1-infected individual carries >104different HTLV-1-infected T cell clones, each with a single-copy provirus integrated in a unique genomic site. We previously showed that the HTLV-1 provirus causes aberrant transcription in the flanking host genome and, by binding the chromatin architectural protein CTCF, forms abnormal chromatin loops with the host genome. However, it remained unknown whether these effects were exerted simply by the presence of the provirus or were induced by its transcription. To answer this question, we sorted HTLV-1-infected T-cell clones into cells positive or negative for proviral plus-strand expression, and then quantified host and provirus transcription using RNA-seq and aberrant chromatin looping using quantitative chromosome conformation capture (q4C) in each cell population. We found that proviral plus-strand transcription induces aberrant transcription and splicing in the flanking genome but suppresses aberrant chromatin loop formation with the nearby host chromatin. Reducing provirus-induced host transcription with an inhibitor of transcriptional elongation allows recovery of chromatin loops in the plus-strand-expressing population. We conclude that aberrant host transcription induced by proviral expression causes temporary, reversible disruption of chromatin looping in the vicinity of the provirus.

show abstract

Section: Discussionmentioning

confidence: 97%

The impact of HTLV-1 expression on the 3D structure and expression of host chromatin

Yaguchi,

Melamed,

Ramanayake

et al. 2023

Preprint

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show abstract

“…Chromatin looping between the HTLV-1 provirus and the host genome is mediated by CTCF binding to the provirus [ 14 ]. We postulated that CTCF binding confers a selective advantage on the provirus; however, the mechanism of this putative advantage is not known.…”

Section: Discussionmentioning

confidence: 99%

The impact of HTLV-1 expression on the 3D structure and expression of host chromatin

Yaguchi,

Melamed,

Ramanayake

et al. 2024

PLoS Pathog

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A typical HTLV-1-infected individual carries >104 different HTLV-1-infected T cell clones, each with a single-copy provirus integrated in a unique genomic site. We previously showed that the HTLV-1 provirus causes aberrant transcription in the flanking host genome and, by binding the chromatin architectural protein CTCF, forms abnormal chromatin loops with the host genome. However, it remained unknown whether these effects were exerted simply by the presence of the provirus or were induced by its transcription. To answer this question, we sorted HTLV-1-infected T-cell clones into cells positive or negative for proviral plus-strand expression, and then quantified host and provirus transcription using RNA-seq, and chromatin looping using quantitative chromosome conformation capture (q4C), in each cell population. We found that proviral plus-strand transcription induces aberrant transcription and splicing in the flanking genome but suppresses aberrant chromatin loop formation with the nearby host chromatin. Reducing provirus-induced host transcription with an inhibitor of transcriptional elongation allows recovery of chromatin loops in the plus-strand-expressing population. We conclude that aberrant host transcription induced by proviral expression causes temporary, reversible disruption of chromatin looping in the vicinity of the provirus.

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“…In such instances, there is a strong precedent for looking beyond the exome and querying the remainder of the genome for SV mutations. Several cases of SV—both typical and atypical (see Cutrupi et al 29 and Boyling et al 87 for a review)—have been reported to cause IPN. Therefore, in the cases where protein-coding mutations cannot be identified, SV represents a possible mutational mechanism that may account for some of the genetically undiagnosed dHMN and other IPN cases.…”

Section: Discussionmentioning

confidence: 99%

Novel gene–intergenic fusion involving ubiquitin E3 ligase UBE3C causes distal hereditary motor neuropathy

Cutrupi

Narayanan

Perez-Siles

et al. 2022

Brain

Self Cite

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Distal hereditary motor neuropathies (dHMNs) are a group of inherited diseases involving the progressive, length-dependent axonal degeneration of the lower motor neurons. There are currently 29 reported causative genes and 4 disease loci implicated in dHMN. Despite the high genetic heterogeneity, mutations in the known genes account for less than 20% of dHMN cases with the mutations identified predominantly being point mutations or indels. We have expanded the spectrum of dHMN mutations with the identification of a 1.35 Mb complex structural variation (SV) causing a form of autosomal dominant dHMN (DHMN1 OMIM %182906). Given the complex nature of SV mutations and the importance of studying pathogenic mechanisms in a neuronal setting, we generated a patient-derived DHMN1 motor neuron model harbouring the 1.35 Mb complex insertion. The DHMN1 complex insertion creates a duplicated copy of the first 10 exons of the ubiquitin-protein E3 ligase gene (UBE3C) and forms a novel gene-intergenic fusion sense transcript by incorporating a terminal pseudo-exon from intergenic sequence within the DHMN1 locus. The UBE3C intergenic fusion (UBE3C-IF) transcript does not undergo nonsense-mediated decay and results in a significant reduction of wild type full length UBE3C (UBE3C-WT) protein levels in DHMN1 iPSC-derived motor neurons. An engineered transgenic C. elegans model expressing the UBE3C-IF transcript in GABA-ergic motor neurons shows neuronal synaptic transmission deficits. Furthermore, the transgenic animals are susceptible to heat stress which may implicate defective protein homeostasis underlying DHMN1 pathogenesis. Identification of the novel UBE3C-IF gene-intergenic fusion transcript in motor neurons highlights a potential new disease mechanism underlying axonal and motor neuron degeneration. These complementary models serve as a powerful paradigm for studying the DHMN1 complex SV and an invaluable tool for defining therapeutic targets for DHMN1.

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Structural Variation at a Disease Mutation Hotspot: Strategies to Investigate Gene Regulation and the 3D Genome

Cited by 9 publications

References 121 publications

The impact of HTLV-1 expression on the 3D structure and expression of host chromatin

The impact of HTLV-1 expression on the 3D structure and expression of host chromatin

The impact of HTLV-1 expression on the 3D structure and expression of host chromatin

Novel gene–intergenic fusion involving ubiquitin E3 ligase UBE3C causes distal hereditary motor neuropathy

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