Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells

Tchasovnikarova, Iva A.; Timms, Richard T.; Matheson, Nicholas J; Wals, Kim; Antrobus, Robin; Göttgens, Berthold; Dougan, Gordon; Dawson, Mark A.; Lehner, Paul J.

doi:10.1126/science.aaa7227

Cited by 279 publications

(460 citation statements)

References 33 publications

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“…+ K9 IP” track), confirming that the same chromatin fragments, from the same cells, are exhibiting both sonication sensitivity and presence of H3K9me3. Euchromatic H3K9me3 domains also contain a majority of sites regulated by the HUSH complex (Tchasovnikarova et al, 2015), an enrichment of 39-fold compared to the srHC subtype (Figure 3D). Indeed, the sites reported to have the greatest dependence on HUSH/SETDB1 for H3K9me3 (Tchasovnikarova et al, 2015) are in euchromatin (Figure S2C).…”

Section: Resultsmentioning

confidence: 99%

“…Euchromatic H3K9me3 domains also contain a majority of sites regulated by the HUSH complex (Tchasovnikarova et al, 2015), an enrichment of 39-fold compared to the srHC subtype (Figure 3D). Indeed, the sites reported to have the greatest dependence on HUSH/SETDB1 for H3K9me3 (Tchasovnikarova et al, 2015) are in euchromatin (Figure S2C). Meanwhile, euchromatic H3K27me3 domains are enriched for transcription factor families (Figure 3C), including all four human HOX gene clusters (e.g., Figure 3E), and are transcriptionally permissive (Figure 3A, E).…”

Section: Resultsmentioning

confidence: 99%

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Genomic and Proteomic Resolution of Heterochromatin and Its Restriction of Alternate Fate Genes

Becker¹,

McCarthy

Sidoli³

et al. 2017

Molecular Cell

182

180

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SUMMARY Heterochromatin is integral to cell identity maintenance by impeding the activation of genes for alternate cell fates. Heterochromatic regions are associated with histone 3 lysine 9 trimethylation (H3K9me3) or H3K27me3, but these modifications are also found in euchromatic regions that permit transcription. We discovered that resistance to sonication is a reliable indicator of the heterochromatin state, and we developed a biophysical method (Gradient-seq) to discriminate subtypes of H3K9me3 and H3K27me3 domains in sonication-resistant heterochromatin (srHC) versus euchromatin. These classifications are more accurate than the histone marks alone in predicting transcriptional silence and resistance of alternate-fate genes to activation during direct cell conversion. Our proteomics of H3K9me3-marked srHC and functional screens revealed diverse proteins, including RBMX and RBMXL1, that impede gene induction during cellular reprogramming. Isolation of srHC with Gradient-seq provides a genome-wide map of chromatin structure, elucidating subtypes of repressed domains that are uniquely predictive of diverse other chromatin properties.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Genomic and Proteomic Resolution of Heterochromatin and Its Restriction of Alternate Fate Genes

Becker¹,

McCarthy

Sidoli³

et al. 2017

Molecular Cell

182

180

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“…For this, we predicted four DNA shape features using simulations: minor groove width (MGW), propeller twist (ProT), roll (Roll), and helix twist (HelT) of DSB sites at base resolution. From each feature, we computed 12 predictors including quantiles (0,10,20,30,40,50,60,70,80,90, and 100%) and the variance to describe the distribution of the feature within a DSB site. We used the resulting 48 variables combined with motif occurrences to predict DSBs with random forests and obtained better accuracy (AUROC = 0.838 and AUPR = 0.915; Fig.…”

Section: Prediction From Dna Motifs and Shapementioning

confidence: 99%

“…We used XRCC4 and γ -H2A.X ChIP-seq for tamoxifen-treated DIvA cells from ArrayExpress accession E-MTAB-1241 [37]. For KBM7 cells, we used DNase-seq from the ChIPAtlas database, and H3K9me3 ChIP-seq from GSE60056 [50]. Instead of KBM7, we used K562 (chronic myelogenous leukemia) for CTCF, H3K4me1/me3 ChIP-seq from the ENCODE project [7] (https://genome.ucsc.…”

Section: Chip-seq and Dnase-seq Datamentioning

confidence: 99%

“…For DNA shape, we computed four features including MGW, ProT, Roll, and HelT of DSB sites at base resolution. For each DNA shape feature, we then computed 12 predictors, including quantiles (0, 10,20,30,40,50,60,70,80,90, and 100%) and the variance to describe the distribution of the feature within a DSB site. The DSB data were next split into two sets: the training set used for learning the model and a test set used for assessing prediction accuracy.…”

Section: Random Forest and Lasso Regressionmentioning

confidence: 99%

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Predicting double-strand DNA breaks using epigenome marks or DNA at kilobase resolution

Mourad

Cuvier

2017

Preprint

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Double-strand breaks (DSBs) result from the attack of both DNA strands by multiple sources, including radiation and chemicals. DSBs can cause the abnormal chromosomal rearrangements associated with cancer. Recent techniques allow the genome-wide mapping of DSBs at high resolution, enabling the comprehensive study of their origins. However, these techniques are costly and challenging. Hence, we devise a computational approach to predict DSBs using the epigenomic and chromatin context, for which public data are readily available from the ENCODE project. We achieve excellent prediction accuracy at high resolution. We identify chromatin accessibility, activity, and long-range contacts as the best predictors.

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An update on post‐transcriptional regulation of retrotransposons

Warkocki

2022

FEBS Letters

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Retrotransposons, including LINE-1, Alu, SVA, and endogenous retroviruses, are one of the major constituents of human genomic repetitive sequences. Through the process of retrotransposition, some of them occasionally insert into new genomic locations by a copy-paste mechanism involving RNA intermediates. Irrespective of de novo genomic insertions, retrotransposon expression can lead to DNA double-strand breaks and stimulate cellular innate immunity through endogenous patterns. As a result, retrotransposons are tightly regulated by multi-layered regulatory processes to prevent the dangerous effects of their expression. In recent years, significant progress was made in revealing how retrotransposon biology intertwines with general posttranscriptional RNA metabolism. Here, I summarize current knowledge on the involvement of post-transcriptional factors in the biology of retrotransposons, focusing on LINE-1. I emphasize general RNA metabolisms such as methylation of adenine (m 6 A), RNA 3 0 -end polyadenylation and uridylation, RNA decay and translation regulation. I discuss the effects of retrotransposon RNP sequestration in cytoplasmic bodies and autophagy. Finally, I summarize how innate immunity restricts retrotransposons and how retrotransposons make use of cellular enzymes, including the DNA repair machinery, to complete their replication cycles.

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Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells

Cited by 279 publications

References 33 publications

Genomic and Proteomic Resolution of Heterochromatin and Its Restriction of Alternate Fate Genes

Genomic and Proteomic Resolution of Heterochromatin and Its Restriction of Alternate Fate Genes

Predicting double-strand DNA breaks using epigenome marks or DNA at kilobase resolution

An update on post‐transcriptional regulation of retrotransposons

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