Nanopore Sequencing Enables Comprehensive Transposable Element Epigenomic Profiling

Molecular Cell, Год журнала: 2020, Номер 80(5), С. 915 - 928.e5

Опубликована: Ноя. 12, 2020

Язык: Английский

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Locus-level L1 DNA methylation profiling reveals the epigenetic and transcriptional interplay between L1s and their integration sites

Cell Genomics, Год журнала: 2024, Номер 4(2), С. 100498 - 100498

Опубликована: Фев. 1, 2024

Long interspersed element 1 (L1) retrotransposons are implicated in human disease and evolution. Their global activity is repressed by DNA methylation, but deciphering the regulation of individual copies has been challenging. Here, we combine short- long-read sequencing to unveil L1 methylation heterogeneity across cell types, families, loci elucidate key principles involved. We find that youngest primate families specifically hypomethylated pluripotent stem cells placenta not most tumors. Locally, intronic intimately associated with gene transcription. Conversely, state can propagate proximal region up 300 bp. This phenomenon accompanied binding specific transcription factors, which drive expression chimeric transcripts. Finally, hypomethylation alone typically insufficient trigger due redundant silencing pathways. Our results illuminate epigenetic transcriptional interplay between their host genome.

Язык: Английский

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Diseases of the nERVous system: retrotransposon activity in neurodegenerative disease

Mobile DNA, Год журнала: 2019, Номер 10(1)

Опубликована: Июль 26, 2019

Transposable Elements (TEs) are mobile genetic elements whose sequences constitute nearly half of the human genome. Each TE copy can be present in hundreds to thousands locations within genome, complicating and genomic studies these highly repetitive sequences. The recent development better tools for evaluating derived has enabled an increasing appreciation contribution TEs disease. While some have contributed novel beneficial host functions, this review will summarize evidence detrimental activity neurodegenerative disorders. Much pathogenicity implicates endogenous retroviruses (ERVs), a subset that entered genome by retroviral infections germline cells our evolutionary ancestors since been passed down as substantial fraction Human specific ERVs (HERVs) represent youngest thus presumed retain greater function resultant pathogenic potential.

Язык: Английский

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Pedigree-based estimation of human mobile element retrotransposition rates

Genome Research, Год журнала: 2019, Номер 29(10), С. 1567 - 1577

Опубликована: Окт. 1, 2019

Germline mutation rates in humans have been estimated for a variety of types, including single-nucleotide and large structural variants. Here, we directly measure the germline retrotransposition rate three active retrotransposon elements: L1, Alu , SVA. We used tools calling mobile element insertions (MEIs) (MELT, RUFUS, TranSurVeyor) on blood-derived whole-genome sequence (WGS) data from 599 CEPH individuals, comprising 33 three-generation pedigrees. identified 26 de novo MEIs 437 births. The estimates elements, one 40 births, is roughly half using phylogenetic analyses, difference magnitude similar to that observed L1 63 births within range previous (1:20–1:200 births). SVA rate, much higher than estimate 900 Our large, pedigrees allowed us assess parent-of-origin effects timing insertion events either gametogenesis or early embryonic development. find statistically significant paternal bias retrotransposition. study represents first in-depth analysis dynamics human WGS

Язык: Английский

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Mouse germ line mutations due to retrotransposon insertions

Mobile DNA, Год журнала: 2019, Номер 10(1)

Опубликована: Апрель 13, 2019

Transposable element (TE) insertions are responsible for a significant fraction of spontaneous germ line mutations reported in inbred mouse strains. This major contribution TEs to the mutational landscape contrasts with situation human, where their relative as insertional mutagens is much lower. In this focussed review, we provide comprehensive lists TE-induced mutations, discuss different TE types involved these and elaborate on particularly interesting cases. We also differences similarities between role mice humans.

Язык: Английский

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Endogenous Double-Stranded RNA

Non-Coding RNA, Год журнала: 2021, Номер 7(1), С. 15 - 15

Опубликована: Фев. 19, 2021

The birth of long non-coding RNAs (lncRNAs) is closely associated with the presence and activation repetitive elements in genome. transcription endogenous retroviruses as well short interspersed not only essential for evolving lncRNAs but also a significant source double-stranded RNA (dsRNA). From an lncRNA-centric point view, latter minor bother context entire cell; however, dsRNA threat. A viral infection cytoplasmic dsRNA, hybrids differ from by 5′ cap structure. Hence, multi-layered defense network place to protect cells infections tolerates structures. first line established compartmentalization; whereas found predominantly confined nucleus mitochondria, exogenous reaches cytoplasm. Here, various sensor proteins recognize features including phosphate group or particular length specific nucleotide sequences. sensors trigger cellular stress pathways innate immunity via interferon signaling induce apoptosis caspase activation. Because its central role recognition immune activation, sensing implicated autoimmune diseases used treat cancer.

Язык: Английский

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Somatic LINE-1 retrotransposition in cortical neurons and non-brain tissues of Rett patients and healthy individuals

PLoS Genetics, Год журнала: 2019, Номер 15(4), С. e1008043 - e1008043

Опубликована: Апрель 11, 2019

Mounting evidence supports that LINE-1 (L1) retrotransposition can occur postzygotically in healthy and diseased human tissues, contributing to genomic mosaicism the brain other somatic tissues of an individual. However, distribution human-specific (L1Hs) insertions their potential impact on carrier cells remain unclear. Here, using a PCR-based targeted bulk sequencing approach, we profiled 9,181 from 20 postmortem five Rett patients matched controls. We identified validated L1Hs both cortical neurons non-brain tissues. In patients, were significantly depleted exons-mainly contributed by long genes-than controls, implying carrying MECP2 mutations might be defenseless against second exonic insertion. observed significant increase compared with same Compared germline insertions, less sense-depleted transcripts, indicating they underwent weaker selective pressure orientation Our observations demonstrate contribute diversity MeCP2 dysfunction alters patterns patients.

Язык: Английский

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No evidence of human genome integration of SARS-CoV-2 found by long-read DNA sequencing

Cell Reports, Год журнала: 2021, Номер 36(7), С. 109530 - 109530

Опубликована: Июль 28, 2021

A recent study proposed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks the LINE-1 (L1) retrotransposition machinery to integrate into DNA of infected cells. If confirmed, this finding could have significant clinical implications. Here, we apply deep (>50×) long-read Oxford Nanopore Technologies (ONT) sequencing HEK293T cells with SARS-CoV-2 and do not find virus integrated genome. By examining ONT data from separate cultivars, completely resolve 78 L1 insertions arising in vitro absence overexpression systems. applied hepatitis B (HBV)-positive liver cancer tissues located a single HBV insertion. These experiments demonstrate reliable resolution retrotransposon exogenous by sequencing. That no evidence integration suggests such events are, at most, extremely rare vivo therefore are unlikely drive oncogenesis or explain post-recovery detection virus.

Язык: Английский

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Transposable elements as new players in neurodegenerative diseases

FEBS Letters, Год журнала: 2021, Номер 595(22), С. 2733 - 2755

Опубликована: Окт. 9, 2021

Neurodegenerative diseases (NDs), including the most prevalent Alzheimer's disease and Parkinson disease, share common pathological features. Despite decades of gene-centric approaches, molecular mechanisms underlying these remain widely elusive. In recent years, transposable elements (TEs), long considered 'junk' DNA, have gained growing interest as pathogenic players in NDs. Age is major risk factor for NDs, several repressive TEs, such heterochromatinization, fail with age. Indeed, heterochromatin relaxation leading to TE derepression has been reported various models neurodegeneration There also evidence that certain proteins involved NDs (e.g., tau, TDP-43) may control expression TEs. The deleterious consequences activation are not well known but they could include DNA damage genomic instability, altered host gene expression, and/or neuroinflammation, which hallmarks aging. TEs might thus represent an overlooked culprit both brain aging neurodegeneration. Certain effects be prevented by inhibiting their activity, pointing novel targets neuroprotection.

Язык: Английский

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Human Endogenous Retroviruses in Neurodegenerative Diseases

Genes, Год журнала: 2024, Номер 15(6), С. 745 - 745

Опубликована: Июнь 5, 2024

Human endogenous retroviruses (HERVs) are DNA transposable elements that have integrated into the human genome via an ancestral germline infection. The potential importance of HERVs is underscored by fact they comprise approximately 8% genome. been implicated in pathogenesis neurodegenerative diseases, a group CNS diseases characterized progressive loss structure and function neurons, resulting cell death multiple physiological dysfunctions. Much evidence indicates initiators or drivers processes sclerosis amyotrophic lateral sclerosis, clinical trials designed to target HERVs. In recent years, role has explored other major including frontotemporal dementia, Alzheimer’s disease Parkinson’s disease, with some interesting discoveries. This review summarizes evaluates past current research on diseases. It discusses manifestation neurodegeneration. critically reviews antiretroviral strategies used therapeutic intervention

Язык: Английский

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