Misexpression of genes lacking CpG islands drives degenerative changes during aging

Lee, Jun-Yeong; Davis, Ian; Youth, Elliot H H; Kim, Jonghwan; Churchill, Gary A.; Godwin, James; Korstanje, Ron; Beck, Samuel J.

doi:10.1126/sciadv.abj9111

Cited by 15 publications

(12 citation statements)

References 84 publications

(130 reference statements)

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“…These data support the model proposed by Lee et al [1], whereby tissue-restricted CGI-gene expressions become increasingly misexpressed during aging, contributing to loss of cellular identity, multiple aging-related pathologies, and ultimately death. Future investigations may identify a subset of CGI-gene misexpressions that can serve as an accurate and convenient measure of the rate of senescent aging at a single timepoint in adults.…”

Section: Discussionsupporting

confidence: 90%

“…Lee et al recently showed [1] that the misexpression of many genes lacking CpG islands (CGI-genes) increases with age in both mice and humans, is higher in patients with aging-associated diseases than in healthy age-matched controls, and is suppressed in aged mice receiving various treatments known to extend lifespan. Lee et al [1] further showed that these CGI-gene misexpressions promote inflammation and the development of degenerative changes, supporting the inflammaging theory of aging [3].…”

Section: Introductionmentioning

confidence: 99%

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Aggregate expression of genes lacking CpG islands increases with age and is positively associated with human mortality

Kerber

O’Brien

Cawthon

2022

Preprint

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In both mice and humans the misexpression of many genes lacking CpG islands (CGI- genes) increases with age, promoting inflammation and degenerative changes (Lee et al. 2021, ref. 1). In light of this recent discovery, we have revisited and expanded upon our previous work on gene expressions vs. aging and mortality in the three-generation CEPH (Centre d'Etudes du Polymorphisme Humain) Utah (CEU) families (Kerber et al. 2009, ref. 2). That study examined gene expressions in lymphoblastoid cell lines (LCLs) established in the early 1980s from all three CEU generations, in relation to age at blood draw, and in relation to the long-term survival of the grandparent generation. The 2009 study did not, however, consider the CGI status of genes, and it excluded from analysis genes not expressed in all of the subjects; therefore, the contribution to variation in age-at-death of inter-individual variation in the misexpression of genes with increasing age was not investigated. For the current study, after categorizing genes by their CGI status (- or +), we now find that most CGI- gene expressions in the LCLs increased with donor age, and after adjustment for donor age and sex, were positively associated with mortality risks. In contrast, most CGI+ gene expressions decreased with donor age, with higher expressions associated with decreased mortality risks. Of 7025 genes with known CGI status with expression detected in sufficient numbers of subjects from the grandparent generation to allow testing of association with mortality, 1834 genes were expressed in all subjects' LCLs across all three generations, and 5191 were expressed in some, but not all subjects. We found the set of "not always expressed" genes to be highly enriched for CGI- genes. Furthermore, 49.4% of the CGI- genes were never expressed from ages 0-14, but expressed sometimes or always at older ages; in contrast, only 22.3% of the CGI+ genes were never expressed from ages 0-14, but expressed at older ages. These data support the model proposed by Lee et al. 2021, whereby tissue-restricted CGI- gene expressions become increasingly misexpressed during aging, contributing to loss of cellular identity, multiple aging-related pathologies, and ultimately death.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Aggregate expression of genes lacking CpG islands increases with age and is positively associated with human mortality

Kerber

O’Brien

Cawthon

2022

Preprint

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“…Evidence indicates that BrdU, upon incorporation into A/T-containing DNA, destabilizes nucleosome positioning through changing DNA structure, and alters chromatin organization and gene expression with induction of cellular senescence in human cells [16][17][18][19][20][21]. Importantly, this notion is in good agreement with the recent report that misexpression of genes lacking CpG islands, which is caused by disrupted chromatin architecture, is a common feature of aged cells [34]. Given that chromatin organization regulates gene expression, the key to the understanding of the action of BrdU lies in the elucidation of the mechanism by which BrdU destabilizes nucleosome positioning.…”

Section: Discussionsupporting

confidence: 87%

“…The N-terminal tail of histone H2B is constituted of 37 amino acid residues in S. cerevisiae [32]. The overall amino acid sequence of the histone H2B N-terminal tail (1-37) is not highly conserved among species; however, its short basic region consisting of eight amino acid residues (30)(31)(32)(33)(34)(35)(36)(37) shows high sequence conservation (Fig. 3A) [33].…”

Section: Regulation Of the Sensitivity To Brdu By The Hbr Domainmentioning

confidence: 99%

The key role of a basic domain of histone H2B N‐terminal tail in the action of 5‐bromodeoxyuridine to induce cellular senescence

Watanabe

Ayusawa

et al. 2022

The FEBS Journal

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5‐Bromodeoxyuridine (BrdU), a thymidine analogue, is an interesting reagent that modulates various biological phenomena. BrdU, upon incorporation into DNA, causes destabilized nucleosome positioning which leads to changes in heterochromatin organization and gene expression in cells. We have previously shown that BrdU effectively induces cellular senescence, a phenomenon of irreversible growth arrest in mammalian cells. Identification of the mechanism of action of BrdU would provide a novel insight into the molecular mechanisms of cellular senescence. Here, we showed that a basic domain in the histone H2B N‐terminal tail, termed the HBR (histone H2B repression) domain, is involved in the action of BrdU. Notably, deletion of the HBR domain causes destabilized nucleosome positioning and derepression of gene expression, as does BrdU. We also showed that the genes up‐regulated by BrdU significantly overlapped with those by deletion of the HBR domain, the result of which suggested that BrdU and deletion of the HBR domain act in a similar way. Furthermore, we showed that decreased HBR domain function induced cellular senescence or facilitated the induction of cellular senescence. These findings indicated that the HBR domain is crucially involved in the action of BrdU, and also suggested that disordered nucleosome organization may be involved in the induction of cellular senescence.

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“…1F , 1G ). We compared DNA methylation levels (ONT-seq) at gene promoters overlapping with CpG islands (CGI promoters), that are associated with housekeeping genes expressed in all cell types, versus non-CGI promoters associated with genes expressed only in specific cell types and located in heterochromatin in non-expressing cell types [55]. DNA methylation at CGI promoters was uniformly low, whereas DNA methylation at non-CGI promoters showed a bimodal distribution of DNA methylation in both euchromatin and heterochromatin and this decreased significantly in Ogt iKO compared to Ctrl Ogt fl mESC ( Fig.…”

Section: Resultsmentioning

confidence: 99%

OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide

Sepulveda,

Li,

Yue

et al. 2024

Preprint

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TheO-GlcNAc transferase OGT interacts robustly with all three mammalian TET methylcytosine dioxygenases. We show here that deletion of theOgtgene in mouse embryonic stem cells (mESC) results in a widespread increase in the TET product 5-hydroxymethylcytosine (5hmC) in both euchromatic and heterochromatic compartments, with concomitant reduction of the TET substrate 5-methylcytosine (5mC) at the same genomic regions. mESC engineered to abolish the TET1-OGT interaction likewise displayed a genome-wide decrease of 5mC. DNA hypomethylation in OGT-deficient cells was accompanied by de-repression of transposable elements (TEs) predominantly located in heterochromatin, and this increase in TE expression was sometimes accompanied by increasedcis-expression of genes and exons located 3’ of the expressed TE. Thus, the TET-OGT interaction prevents DNA demethylation and TE expression in heterochromatin by restraining TET activity genome-wide. We suggest that OGT protects the genome against DNA hypomethylation and impaired heterochromatin integrity, preventing the aberrant increase in TE expression observed in cancer, autoimmune-inflammatory diseases, cellular senescence and ageing.

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Misexpression of genes lacking CpG islands drives degenerative changes during aging

Abstract: Disrupted nuclear architecture triggers misexpression of genes lacking CpG islands and physiological deterioration during aging.

Cited by 15 publications

References 84 publications

Aggregate expression of genes lacking CpG islands increases with age and is positively associated with human mortality

Aggregate expression of genes lacking CpG islands increases with age and is positively associated with human mortality

The key role of a basic domain of histone H2B N‐terminal tail in the action of 5‐bromodeoxyuridine to induce cellular senescence

OGT prevents DNA demethylation and suppresses the expression of transposable elements in heterochromatin by restraining TET activity genome-wide

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