Many Different LINE-1 Retroelements Are Activated in Bladder Cancer

Whongsiri, Patcharawalai; Goering, Wolfgang; Lautwein, Tobias; Hader, Christiane; Niegisch, Günter; Köhrer, Karl; Hoffmann, Michèle J.; Schulz, Wolfgang A.

doi:10.3390/ijms21249433

Cited by 10 publications

(9 citation statements)

References 45 publications

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“…This gene is located on chromosome 22 and harbors seven intronic, full-length L1 elements (Figure 7A ). One locus, L1-5219, has been previously characterized as an unusually active locus that is expressed in multiple cancers ( 21 , 22 , 29 , 30 , 32 , 64 , 110 ). L1-5219 shows consistent mRNA expression across multiple cancer cell lines with 26 mapped reads in MCF7 cells, 4 mapped reads in HeLa cells, and 49 mapped reads in HEK293 cells, despite the very low mappability of this element.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have determined that each cell type expresses only a small and fairly unique subset of genomic L1 loci ( 21 , 64 , 116 ). A strict, organ-specific expression of L1 loci is also observed in vivo ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

“…Even in a cell line like MCF7 that supports some of the highest levels of L1 mRNA expression, only 3% of L1 loci express moderately (Figure 1B ). Based on the finding that methylation can suppress L1 promoter function ( 38 , 39 ), a large number of previous studies have often assumed that global hypomethylation and histone activating marks at L1 promoters correlate with L1 expression ( 36 , 38 , 48 , 64 , 117–119 ). Our findings demonstrate that the sensitivity of those studies is often insufficient to correlate epigenetic marks with L1 expression because they were investigating the state of the small group of expressed L1 elements (∼50–100) pooled together with a large set of thousands of unexpressed L1 loci.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of epigenetic features characteristic of L1 loci expressed in human cells

Freeman

White

Stow

et al. 2022

Nucleic Acids Research

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Only a select few L1 loci in the human genome are expressed in any given cell line or organ, likely to minimize damage done to the genome. The epigenetic features and requirements of expressed L1 loci are currently unknown. Using human cells and comprehensive epigenetic analysis of individual expressed and unexpressed L1 loci, we determined that endogenous L1 transcription depends on a combination of epigenetic factors, including open chromatin, activating histone modifications, and hypomethylation at the L1 promoter. We demonstrate that the L1 promoter seems to require interaction with enhancer elements for optimal function. We utilize epigenetic context to predict the expression status of L1Hs loci that are poorly mappable with RNA-Seq. Our analysis identified a population of ‘transitional’ L1 loci that likely have greater potential to be activated during the epigenetic dysregulation seen in tumors and during aging because they are the most responsive to targeted CRISPR-mediated delivery of trans-activating domains. We demonstrate that an engineered increase in endogenous L1 mRNA expression increases Alu mobilization. Overall, our findings present the first global and comprehensive analysis of epigenetic status of individual L1 loci based on their expression status and demonstrate the importance of epigenetic context for L1 expression heterogeneity.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Analysis of epigenetic features characteristic of L1 loci expressed in human cells

Freeman

White

Stow

et al. 2022

Nucleic Acids Research

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“…Generally repressed in somatic cells, L1s are activated in the embryo, and the de novo retrotransposition events in the germline by highly polymorphic L1s may contribute to heritable genetic variations and mutations. Since the reactivation of L1s in the germline and the loss of global DNA methylation threatens the stability of the germline genome, L1s are usually silenced by adaptive mechanisms in the germline [ 707 , 708 ], whereas derepression causing global hypomethylation of LINE1 is associated with many types of cancers [ 679 , 709 , 710 , 711 ]. The only known somatic tissue in humans where L1s are derepressed throughout the entire life cycle is the human brain [ 712 ].…”

Section: Melatonin Regulates Sars-cov-2-mediated Crosstalk Between Th...mentioning

confidence: 99%

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Loh¹,

Reíter

2022

IJMS

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The relentless, protracted evolution of the SARS-CoV-2 virus imposes tremendous pressure on herd immunity and demands versatile adaptations by the human host genome to counter transcriptomic and epitranscriptomic alterations associated with a wide range of short- and long-term manifestations during acute infection and post-acute recovery, respectively. To promote viral replication during active infection and viral persistence, the SARS-CoV-2 envelope protein regulates host cell microenvironment including pH and ion concentrations to maintain a high oxidative environment that supports template switching, causing extensive mitochondrial damage and activation of pro-inflammatory cytokine signaling cascades. Oxidative stress and mitochondrial distress induce dynamic changes to both the host and viral RNA m6A methylome, and can trigger the derepression of long interspersed nuclear element 1 (LINE1), resulting in global hypomethylation, epigenetic changes, and genomic instability. The timely application of melatonin during early infection enhances host innate antiviral immune responses by preventing the formation of “viral factories” by nucleocapsid liquid-liquid phase separation that effectively blockades viral genome transcription and packaging, the disassembly of stress granules, and the sequestration of DEAD-box RNA helicases, including DDX3X, vital to immune signaling. Melatonin prevents membrane depolarization and protects cristae morphology to suppress glycolysis via antioxidant-dependent and -independent mechanisms. By restraining the derepression of LINE1 via multifaceted strategies, and maintaining the balance in m6A RNA modifications, melatonin could be the quintessential ancient molecule that significantly influences the outcome of the constant struggle between virus and host to gain transcriptomic and epitranscriptomic dominance over the host genome during acute infection and PASC.

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“…This is because during the analysis of ATAC-seq, DNA accessibility is probed with a hyperactive Tn5 transposase, which allows to simultaneously fragment and integrate the sequencing adapters preferentially in functional regions with accessible chromatin [13]. ATAC-seq has been widely adopted to investigate the pathophysiologic mechanisms of various tumors [14,15].…”

Section: Introductionmentioning

confidence: 99%

Global changes in chromatin accessibility and transcription in growth hormone-secreting pituitary adenoma

Wang

Zhang

et al. 2022

Endocrine

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Purpose Growth hormone-secreting pituitary adenoma (GHPA) is an insidious disease with persistent hypersecretion of growth hormone and insulin-like growth factor 1, causing increased morbidity and mortality. Previous studies have investigated the transcription of GHPA. However, the gene regulatory landscape has not been fully characterized. The objective of our study was to unravel the changes in chromatin accessibility and transcription in GHPA. Methods Six patients diagnosed with GHPA in the Department of Neurosurgery at Huashan Hospital were enrolled in our study. Primary pituitary adenoma tissues and adjacent normal pituitary specimens with no morphologic abnormalities from these six patients were obtained at surgery. RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) were applied to investigate the underlying relationship between gene expression and chromatin accessibility changes in GHPA. Results Totally, 1528 differential expression genes (DEGs) were identified by transcriptomics analyses, including 725 up-regulated and 803 down-regulated. Further, we obtained 64 significantly DEGs including 10 DEGs were elevated and 54 DEGs were negligibly expressed in tumors tissues. The up-regulated DEGs were mainly involved in terms related to synapse formation, nervous system development and secretory pathway. In parallel, 3916 increased and 2895 decreased chromatin-accessible regions were mapped by ATAC-seq. Additionally, the chromatin accessible changes were frequently located adjacent to transcription factor CTCF and Rfx2 binding site. Conclusions Our results are the first to demonstrate the landscape of chromatin accessibility in GHPA, which may contribute to illustrate the underlying transcriptional regulation mechanism of this disease.

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Many Different LINE-1 Retroelements Are Activated in Bladder Cancer

Cited by 10 publications

References 45 publications

Analysis of epigenetic features characteristic of L1 loci expressed in human cells

Analysis of epigenetic features characteristic of L1 loci expressed in human cells

Melatonin: Regulation of Viral Phase Separation and Epitranscriptomics in Post-Acute Sequelae of COVID-19

Global changes in chromatin accessibility and transcription in growth hormone-secreting pituitary adenoma

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