Age-associated bimodal transcriptional drift reduces intergenic disparities in transcription

Min, Byungkuk; Park, Myungsun; Jeon, Kyuheum; Park, Jung Tak; Seo, Hyemyung; Jeong, Sangkyun; Kang, Yong-Kook

doi:10.18632/aging.101428

Cited by 6 publications

(8 citation statements)

References 64 publications

(72 reference statements)

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“…Supposing that DNA methylation is the primary mechanism regulating the transcription of genes in the corresponding regions, the LOM events in regions with heavy methylation may make the promoters more accessible to transcriptional activators, whereas the GOM events in the hypomethylated regions may make the promoters more and more occupied by repressors. This condition most likely results in a bimodal transcriptional drift, where the genes that are weakly expressed in the young animals are increasingly transcribed in older animals; in contrast, the genes that are highly expressed in the young animals are gradually downregulated with age (Min, Park, Jeon, et al, ). Our observation of age‐associated epigenetic drift therefore lends sound support to the bimodal transcriptional drift theory and is consistent with the general view that aging reflects a stochastic process of increasing disorder.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 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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Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…Genomic DNA was extracted from tissues and cells with Multisource Genomic DNA miniprep kit (Axygen). For measuring telomere length, quantitative real-time PCR methods were used as previously described (Cawthon, 2009; Min et al, 2018).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrion-processed TERC regulates senescence without affecting telomerase activities

et al. 2019

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Mitochondrial dysfunctions play major roles in ageing. How mitochondrial stresses invoke downstream responses and how specificity of the signaling is achieved, however, remains unclear. We have previously discovered that the RNA component of Telomerase TERC is imported into mitochondria, processed to a shorter form TERC-53 , and then exported back to the cytosol. Cytosolic TERC-53 levels respond to mitochondrial functions, but have no direct effect on these functions, suggesting that cytosolic TERC-53 functions downstream of mitochondria as a signal of mitochondrial functions. Here, we show that cytosolic TERC-53 plays a regulatory role on cellular senescence and is involved in cognition decline in 10 months old mice, independent of its telomerase function. Manipulation of cytosolic TERC-53 levels affects cellular senescence and cognition decline in 10 months old mouse hippocampi without affecting telomerase activity, and most importantly, affects cellular senescence in terc −/− cells. These findings uncover a senescence-related regulatory pathway with a non-coding RNA as the signal in mammals. Electronic supplementary material The online version of this article (10.1007/s13238-019-0612-5) contains supplementary material, which is available to authorized users.

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“…We examined the genes ( n = 154) encoding effector enzymes and mediators that directly participate in the modification of nucleosomes ( Park et al, 2017 ; Min et al, 2018 ). Table 2 presents the differentially expressed epidriver genes between the SH and SL samples in the ADCs and SCCs ( p < 1 × 10 –7 in either ADCs or SCCs (also see Supplementary Table S5 ).…”

Section: Resultsmentioning

confidence: 99%

“…The genes belonging to the DNA methylation category also showed a significant difference between the SH and SL samples ( Table 1 ), with the highest root-mean-square deviation (RMSD) value among the “HISTONE_MODIFICATION” sub-categories ( Supplementary Figure S5 ), which measures how far off the genes in the cancer samples are from those in the normal samples in terms of the mean expression levels ( Kwon et al, 2015 ; Min et al, 2018 ). We observed that DNA methyltransferase genes such as DNMT1, DNMT3A , and DNMT3B were overrepresented in all cancer groups, with a significant difference between the SH and SL samples in both ADCs and SCCs ( Figure 6A and also see Table 2 ), which prompted us to explore the genome for the methylation states.…”

Section: Resultsmentioning

confidence: 99%

SETDB1 Overexpression Sets an Intertumoral Transcriptomic Divergence in Non-small Cell Lung Carcinoma

Kang

Min

2020

Front. Genet.

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An increasing volume of evidence suggests that SETDB1 plays a role in the tumorigenesis of various cancers, classifying SETDB1 as an oncoprotein. However, owing to its numerous protein partners and their global-scale effects, the molecular mechanism underlying SETDB1-involved oncogenesis remains ambiguous. In this study, using public transcriptome data of lung adenocarcinoma (ADC) and squamous-cell carcinoma (SCC), we compared tumors with high-level SETDB1 (SH) and those with low-level SETDB1 (comparable with normal samples; SL). The results of principal component analysis revealed a transcriptomic distinction and divergence between the SH and SL samples in both ADCs and SCCs. The results of gene set enrichment analysis indicated that genes involved in the “epithelial–mesenchymal transition,” “innate immune response,” and “autoimmunity” collections were significantly depleted in SH tumors, whereas those involved in “RNA interference” collections were enriched. Chromatin-modifying genes were highly expressed in SH tumors, and the variance in their expression was incomparably high in SCC-SH, which suggested greater heterogeneity within SCC tumors. DNA methyltransferase genes were also overrepresented in SH samples, and most differentially methylated CpGs (SH/SL) were undermethylated in a highly biased manner in ADCs. We identified interesting molecular signatures associated with the possible roles of SETDB1 in lung cancer. We expect these SETDB1-associated molecular signatures to facilitate the development of biologically relevant targeted therapies for particular types of lung cancer.

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Age-associated bimodal transcriptional drift reduces intergenic disparities in transcription

Cited by 6 publications

References 64 publications

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

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

Mitochondrion-processed TERC regulates senescence without affecting telomerase activities

SETDB1 Overexpression Sets an Intertumoral Transcriptomic Divergence in Non-small Cell Lung Carcinoma

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