Replicative senescence is associated with nuclear reorganization and with DNA methylation at specific transcription factor binding sites

Clinical Epigenetics
Sonja HänzelmannWolfgang Wagner

Abstract

Primary cells enter replicative senescence after a limited number of cell divisions. This process needs to be considered in cell culture experiments, and it is particularly important for regenerative medicine. Replicative senescence is associated with reproducible changes in DNA methylation (DNAm) at specific sites in the genome. The mechanism that drives senescence-associated DNAm changes remains unknown - it may involve stochastic DNAm drift due to imperfect maintenance of epigenetic marks or it is directly regulated at specific sites in the genome. In this study, we analyzed the reorganization of nuclear architecture and DNAm changes during long-term culture of human fibroblasts and mesenchymal stromal cells (MSCs). We demonstrate that telomeres shorten and shift towards the nuclear center at later passages. In addition, DNAm profiles, either analyzed by MethylCap-seq or by 450k IlluminaBeadChip technology, revealed consistent senescence-associated hypermethylation in regions associated with H3K27me3, H3K4me3, and H3K4me1 histone marks, whereas hypomethylation was associated with chromatin containing H3K9me3 and lamina-associated domains (LADs). DNA hypermethylation was significantly enriched in the vicinity of genes that ar...Continue Reading

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Citations

Feb 9, 2016·Neuroscience·S KálmánK Mirnics
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Apr 20, 2019·Frontiers in Genetics·Wolfgang Wagner
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Mar 24, 2021·Briefings in Functional Genomics·Azucena RochaNicola Neretti
May 21, 2021·Communications Biology·Julia FranzenWolfgang Wagner

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Datasets Mentioned

BETA
GSE59960
GSE59966

Methods Mentioned

BETA
methyl-capture sequencing
MethylCap-seq
in
pull down
methyl-capture
electrophoresis
RNA-Seq
ChIP-Seq

Software Mentioned

DESeq2
GenometriCorr Package
Flexbar
Tophat2
Definiens XD
Ensemble
Bowtie2
HTSeq

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