Locus-specific chromatin profiling of evolutionarily young transposable elements

Taylor, Darren; Lowe, Robert; Philippe, Claude; Cheng, Kevin; Cristofari, Gaël; Branco, Miguel R.

doi:10.1101/2021.08.25.457666

Cited by 4 publications

(5 citation statements)

References 88 publications

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“…4 E and F). This evidence taken together with recent reports of epigenetic signatures driving L1 expression [29,66] suggests epigenomic characteristics unique to Round Spermatids, such as the initiation of histone-protamine exchange (Additional file 4 A2 and B2), may facilitate an increase in L1 expression during this stage of Spermatogenesis.…”

Section: Discussionsupporting

confidence: 68%

SCIFER: approach for analysis of LINE-1 mRNA expression in single cells at a single locus resolution

et al. 2022

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Background Endogenous expression of L1 mRNA is the first step in an L1-initiated mutagenesis event. However, the contribution of individual cell types to patterns of organ-specific L1 mRNA expression remains poorly understood, especially at single-locus resolution. We introduce a method to quantify expression of mobile elements at the single-locus resolution in scRNA-Seq datasets called Single Cell Implementation to Find Expressed Retrotransposons (SCIFER). SCIFER aligns scRNA-Seq reads uniquely to the genome and extracts alignments from single cells by cell-specific barcodes. In contrast to the alignment performed using default parameters, this alignment strategy increases accuracy of L1 locus identification by retaining only reads that are uniquely mapped to individual L1 loci. L1 loci expressed in single cells are unambiguously identified using a list of L1 loci manually validated to be expressed in bulk RNA-Seq datasets generated from the same cell line or organ. Results Validation of SCIFER using MCF7 cells determined technical parameters needed for optimal detection of L1 expression in single cells. We show that unsupervised analysis of L1 expression in single cells exponentially inflates both the levels of L1 expression and the number of expressed L1 loci. Application of SCIFER to analysis of scRNA-Seq datasets generated from mouse and human testes identified that mouse Round Spermatids and human Spermatogonia, Spermatocytes, and Round Spermatids express the highest levels of L1 mRNA. Our analysis also determined that similar to mice, human testes from unrelated individuals share as much as 80% of expressed L1 loci. Additionally, SCIFER determined that individual mouse cells co-express different L1 sub-families and different families of transposable elements, experimentally validating their co-existence in the same cell. Conclusions SCIFER detects mRNA expression of individual L1 loci in single cells. It is compatible with scRNA-Seq datasets prepared using traditional sequencing methods. Validated using a human cancer cell line, SCIFER analysis of mouse and human testes identified key cell types supporting L1 expression in these species. This will further our understanding of differences and similarities in endogenous L1 mRNA expression patterns in mice and humans.

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Section: Discussionsupporting

confidence: 68%

SCIFER: approach for analysis of LINE-1 mRNA expression in single cells at a single locus resolution

et al. 2022

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“…This analysis also confirmed that methylation levels of the first 15 CpG reflect those of the entire L1 CpG island (Figure S1I). At the genome-wide level, we also cross-validated bs-ATLAS-seq by a combination of Hi-C with methylated DNA immunoprecipitation (Hi-MeDIP) 74 . Thus, bs-ATLAS-seq is a cost-effective method to accurately profile L1 position and methylation genome-wide.…”

Section: Genome-wide and Locus-specific Human L1 Dna Methylation Prof...mentioning

confidence: 99%

Comprehensive locus-specific L1 DNA methylation profiling reveals the epigenetic and transcriptional interplay between L1s and their integration sites

Lanciano

Philippe

Sarkar

et al. 2023

Preprint

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SUMMARYPrimate-specific long interspersed elements-1 (LINE-1 or L1) play important roles in human disease and evolution, but are difficult to study given their repetitive nature. Here, we combine short- and long-read sequencing to resolve the DNA methylation profiles of L1 elements genome-wide and at single-locus resolution. With this approach, we uncover cell-type-, family- and locus-specific patterns. We show that the methylation of intragenic L1 elements is associated with gene body methylation of transcriptionally active genes and conversely, that L1s frequently propagate their methylation state to the surrounding genomic region. We identify sets of transcription factors bound to unmethylated L1s and their flank, some of which control the expression of chimeric gene-retrotransposon transcripts. Finally, we demonstrate that hypomethylation alone is insufficient to unleash L1 expression. Together, our results highlight the interplay between L1 retrotransposons and their integration sites, and reveal unanticipated layers of cell-type-specific epigenetic regulation.HIGHLIGHTSAggregate analysis masks the heterogeneity of L1 DNA methylationThe region immediately adjacent to an L1 insertion frequently adopts the L1 methylation stateWidespread L1-associated epivariation is accompanied by differential transcription factor binding and new transcript isoformsL1 hypomethylation alone is insufficient to enable its transcription

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“…More globally, a major problem with ChIP-seq reads in the identification of associated TE sequences is their short sizes which prevents obtaining a sufficient number of reads unambiguously mapped to individual TE locations. Very recently, a solution has been proposed to help bypass this difficulty which takes advantage of random 3D interactions as implemented in the pipeline PatChER (Taylor et al, 2021). These random interactions correspond to relatively short distance (few tens of kb) 3D folding of the chromosomes and can be obtained from high throughput technologies like HiC-seq.…”

Section: Chromatin Structure and Chromosome-chromosome Interactionsmentioning

confidence: 99%

“…The principle of this method is that since HiC-seq produces chimeric fragments between genomic regions that are close in 3D space, it should thus be possible to pair non-unique reads with unique reads from nearby genomic regions when focusing on random 3D interactions. By applying their method on mouse embryonic stem cell data, the authors were able to show that a particular family of retrotransposon displays a large variation in the enrichment of an active histone modifications according to the genomic location of the TE insertions (Taylor et al, 2021).…”

Section: Chromatin Structure and Chromosome-chromosome Interactionsmentioning

confidence: 99%

Recent Bioinformatic Progress to Identify Epigenetic Changes Associated to Transposable Elements

Lerat

2022

Front. Genet.

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Transposable elements (TEs) are recognized for their great impact on the functioning and evolution of their host genomes. They are associated to various deleterious effects, which has led to the evolution of regulatory epigenetic mechanisms to control their activity. Despite these negative effects, TEs are also important actors in the evolution of genomes by promoting genetic diversity and new regulatory elements. Consequently, it is important to study the epigenetic modifications associated to TEs especially at a locus-specific level to determine their individual influence on gene functioning. To this aim, this short review presents the current bioinformatic tools to achieve this task.

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Locus-specific chromatin profiling of evolutionarily young transposable elements

Cited by 4 publications

References 88 publications

SCIFER: approach for analysis of LINE-1 mRNA expression in single cells at a single locus resolution

SCIFER: approach for analysis of LINE-1 mRNA expression in single cells at a single locus resolution

Comprehensive locus-specific L1 DNA methylation profiling reveals the epigenetic and transcriptional interplay between L1s and their integration sites

Recent Bioinformatic Progress to Identify Epigenetic Changes Associated to Transposable Elements

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