Surveillance of Retroelement Expression and Nucleic‐Acid Immunity by Histone Methyltransferase SETDB1

Kang, Yong‐Kook

doi:10.1002/bies.201800058

Cited by 14 publications

(18 citation statements)

References 92 publications

(139 reference statements)

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“…It hints at a correlation between the establishment of global H3K9 methylation and the suppression of retroelements. In reality, in somatic and embryonic stem cells, SETDB1/Trim28/KRAB-ZNF-mediated H3K9 methylation, separately from or in combination with DNA methylation, represses certain retroelement families ( 69 , 70 ). Additionally, LINE1 sequences are repressed in a target-specific fashion in the experiment using the TALE-L1-KRAB construct in mouse embryos ( 21 ).…”

Section: Discussionmentioning

confidence: 99%

Dnmt1 binds and represses genomic retroelements via DNA methylation in mouse early embryos

Min

Jeong

Jeon

et al. 2020

Nucleic Acids Research

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Genome-wide passive DNA demethylation in cleavage-stage mouse embryos is related to the cytoplasmic localization of the maintenance methyltransferase DNMT1. However, recent studies provided evidences of the nuclear localization of DNMT1 and its contribution to the maintenance of methylation levels of imprinted regions and other genomic loci in early embryos. Using the DNA adenine methylase identification method, we identified Dnmt1-binding regions in four- and eight-cell embryos. The unbiased distribution of Dnmt1 peaks in the genic regions (promoters and CpG islands) as well as the absence of a correlation between the Dnmt1 peaks and the expression levels of the peak-associated genes refutes the active participation of Dnmt1 in the transcriptional regulation of genes in the early developmental period. Instead, Dnmt1 was found to associate with genomic retroelements in a greatly biased fashion, particularly with the LINE1 (long interspersed nuclear elements) and ERVK (endogenous retrovirus type K) sequences. Transcriptomic analysis revealed that the transcripts of the Dnmt1-enriched retroelements were overrepresented in Dnmt1 knockdown embryos. Finally, methyl-CpG-binding domain sequencing proved that the Dnmt1-enriched retroelements, which were densely methylated in wild-type embryos, became demethylated in the Dnmt1-depleted embryos. Our results indicate that Dnmt1 is involved in the repression of retroelements through DNA methylation in early mouse development.

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Section: Discussionmentioning

confidence: 99%

Dnmt1 binds and represses genomic retroelements via DNA methylation in mouse early embryos

Min

Jeong

Jeon

et al. 2020

Nucleic Acids Research

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“…In addition to DNA methylation, histone methylation contributes to the repression of genomic retroelements. Retroelements are controlled by histone H3 lysine 9 methylation (H3K9me) catalyzed by SETDB1 [see (Kang, ) and references therein], G9A/GLP (Maksakova et al, ), and SUV39H1 and SUV39H2 (Bulut‐Karslioglu et al, ), and/or by H3 lysine 27 methylation (H3K27me) performed by the PRC2 complex involving EZH2 (Leeb et al, ). However, a recent study (Min, Park, Jeon, et al, ) has suggested that the expression levels of epi‐driver genes encoding these histone‐modifying enzymes and other related epigenetic modifiers were relatively stable and had little change during skeletal muscle aging.…”

Section: Discussionmentioning

confidence: 99%

“…Sedivy et al proposed an “aging‐by‐transposition” model, in which the retroelements and their transposases are the primary causes of structural dysregulation in the genome to manifest the aging phenotypes (Sedivy et al, ). It is notable that retroelement expression and transposition are also associated with cancer development (Kang, ; Lee et al, ) and neurodegenerative diseases (Reilly, Faulkner, Dubnau, Ponomarev, & Gage, ; Tan et al, ).…”

Section: Introductionmentioning

confidence: 99%

Demethylation and derepression of genomic retroelements in the skeletal muscles of aged mice

2019

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Changes in DNA methylation influence the aging process and contribute to aging phenotypes, but few studies have been conducted on DNA methylation changes in conjunction with skeletal muscle aging. We explored the DNA methylation changes in a variety of retroelement families throughout aging (at 2, 20, and 28 months of age) in murine skeletal muscles by methyl‐binding domain sequencing (MBD‐seq). The two following contrasting patterns were observed among the members of each repeat family in superaged mice: (a) hypermethylation in weakly methylated retroelement copies and (b) hypomethylation in copies with relatively stronger methylation levels, representing a pattern of “regression toward the mean” within a single retroelement family. Interestingly, these patterns depended on the sizes of the copies. While the majority of the elements showed a slight increase in methylation, the larger copies (>5 kb) displayed evident demethylation. All these changes were not observed in T cells. RNA sequencing revealed a global derepression of retroelements during the late phase of aging (between 20 and 28 months of age), which temporally coincided with retroelement demethylation. Following this methylation drift trend of “regression toward the mean,” aging tended to progressively lose the preexisting methylation differences and local patterns in the genomic regions that had been elaborately established during the early period of development.

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“…A possible explanation may be that HERV elements (and, by extension, HERV-derived REs) are subject to strong epigenetic controls that keep them essentially silent, except in cancer, autoimmunity and placental development (Hurst & Magiorkinis, 2017). Another explanation may be based on a recent report (Kang, 2018) suggesting that tumour-initiating cells must have repressed HERV elements, since their expression produces different types of RNAs that elicit interferon response and apoptosis, leading to cancer cell death. On the other hand, HERV silencing enables cancer protection against lethal drug exposure, promotes immune evasion, and progresses to fully established cancer.…”

Section: Discussionmentioning

confidence: 99%

Biomarker potential of repetitive-element transcriptome in lung cancer

Arroyo

Bautista

Larrosa

et al. 2019

PeerJ

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Since repetitive elements (REs) account for nearly 53% of the human genome, profiling its transcription after an oncogenic change might help in the search for new biomarkers. Lung cancer was selected as target since it is the most frequent cause of cancer death. A bioinformatic workflow based on well-established bioinformatic tools (such as RepEnrich, RepBase, SAMTools, edgeR and DESeq2) has been developed to identify differentially expressed RNAs from REs. It was trained and tested with public RNA-seq data from matched sequencing of tumour and healthy lung tissues from the same patient to reveal differential expression within the RE transcriptome. Healthy lung tissues express a specific set of REs whose expression, after an oncogenic process, is strictly and specifically changed. Discrete sets of differentially expressed REs were found for lung adenocarcinoma, for small-cell lung cancer, and for both cancers. Differential expression affects more HERV-than LINE-derived REs and seems biased towards down-regulation in cancer cells. REs behaving consistently in all patients were tested in a different patient cohort to validate the proposed biomarkers. Down-regulation of AluYg6 and LTR18B was confirmed as potential lung cancer biomarkers, while up-regulation of HERVK11D-Int is specific for lung adenocarcinoma and up-regulation of UCON88 is specific for small cell lung cancer. Hence, the study of RE transcriptome might be considered another research target in cancer, making REs a promising source of lung cancer biomarkers.

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Surveillance of Retroelement Expression and Nucleic‐Acid Immunity by Histone Methyltransferase SETDB1

Cited by 14 publications

References 92 publications

Dnmt1 binds and represses genomic retroelements via DNA methylation in mouse early embryos

Dnmt1 binds and represses genomic retroelements via DNA methylation in mouse early embryos

Demethylation and derepression of genomic retroelements in the skeletal muscles of aged mice

Biomarker potential of repetitive-element transcriptome in lung cancer

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