Chromatin modifier HUSH co-operates with RNA decay factor NEXT to restrict transposable element expression

Molecular Cell, Journal Year: 2022, Volume and Issue: 82(9), P. 1691 - 1707.e8

Published: March 28, 2022

Transposable elements (TEs) are widespread genetic parasites known to be kept under tight transcriptional control. Here, we describe a functional connection between the mouse-orthologous "nuclear exosome targeting" (NEXT) and "human silencing hub" (HUSH) complexes, involved in nuclear RNA decay epigenetic of TEs, respectively. Knocking out NEXT component ZCCHC8 embryonic stem cells results elevated TE levels. We identify physical interaction MPP8 protein HUSH establish that recruits chromatin at MPP8-bound loci. However, while both dampen expression, their activities predominantly affect shorter non-polyadenylated full-length polyadenylated transcripts, Indeed, our data suggest repressive action promotes condition favoring activity. In this way, post-transcriptional machineries synergize suppress genotoxic potential RNAs.

Language: Английский

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Transient naive reprogramming corrects hiPS cells functionally and epigenetically

Nature, Journal Year: 2023, Volume and Issue: 620(7975), P. 863 - 872

Published: Aug. 16, 2023

Cells undergo a major epigenome reconfiguration when reprogrammed to human induced pluripotent stem cells (hiPS cells). However, the epigenomes of hiPS and embryonic (hES) differ significantly, which affects cell function1-8. These differences include epigenetic memory aberrations that emerge during reprogramming, for mechanisms remain unknown. Here we characterized persistence emergence these by performing genome-wide DNA methylation profiling throughout primed naive reprogramming somatic cells. We found reprogramming-induced midway through whereas demethylation begins early in reprogramming. Using this knowledge, developed transient-naive-treatment (TNT) strategy emulates reset. show is concentrated origin-dependent repressive chromatin marked H3K9me3, lamin-B1 aberrant CpH methylation. TNT reconfigures domains hES cell-like state does not disrupt genomic imprinting. an isogenic system, demonstrate can correct transposable element overexpression differential gene expression seen conventional cells, TNT-reprogrammed similar differentiation efficiencies. Moreover, enhances derived from multiple types. Thus, corrects aberrations, producing are molecularly functionally more than foresee becoming new standard biomedical therapeutic applications providing novel system studying memory.

Language: Английский

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Resolution of structural variation in diverse mouse genomes reveals chromatin remodeling due to transposable elements

Cell Genomics, Journal Year: 2023, Volume and Issue: 3(5), P. 100291 - 100291

Published: April 6, 2023

Diverse inbred mouse strains are important biomedical research models, yet genome characterization of many is fundamentally lacking in comparison with humans. In particular, catalogs structural variants (SVs) (variants ≥ 50 bp) incomplete, limiting the discovery causative alleles for phenotypic variation. Here, we resolve genome-wide SVs 20 genetically distinct mice long-read sequencing. We report 413,758 site-specific affecting 13% (356 Mbp) reference assembly, including 510 previously unannotated coding variants. substantially improve

Language: Английский

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Towards targeting transposable elements for cancer therapy

Nature reviews. Cancer, Journal Year: 2024, Volume and Issue: 24(2), P. 123 - 140

Published: Jan. 16, 2024

Language: 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, Journal Year: 2024, Volume and Issue: 4(2), P. 100498 - 100498

Published: Feb. 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.

Language: Английский

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