Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements

Aging Cell

Marco De Cecco¹  Steven W. Criscione¹  Edward J. Peckham¹  Sara Hillenmeyer¹  Eliza A. Hamm¹  Jayameenakshi Manivannan¹  Abigail L. Peterson¹  Jill A. Kreiling¹  Nicola Neretti¹ 

[1] Department of Molecular Biology, Cell Biology and Biochemistry, Center for Genomics and Proteomics, Brown University, Providence, RI, USA

关键词: aging;    cellular senescence;    chromatin;    epigenetics;    transposable elements;   

DOI  :  10.1111/acel.12047

来源: Wiley

【 摘 要 】

Summary

Replicative cellular senescence is an important tumor suppression mechanism and also contributes to aging. Progression of both cancer and aging include significant epigenetic components, but the chromatin changes that take place during cellular senescence are not known. We used formaldehyde assisted isolation of regulatory elements (FAIRE) to map genome-wide chromatin conformations. In contrast to growing cells, whose genomes are rich with features of both open and closed chromatin, FAIRE profiles of senescent cells are significantly smoothened. This is due to FAIRE signal loss in promoters and enhancers of active genes, and FAIRE signal gain in heterochromatic gene-poor regions. Chromatin of major retrotransposon classes, Alu, SVA and L1, becomes relatively more open in senescent cells, affecting most strongly the evolutionarily recent elements, and leads to an increase in their transcription and ultimately transposition. Constitutive heterochromatin in centromeric and peri-centromeric regions also becomes relatively more open, and the transcription of satellite sequences increases. The peripheral heterochromatic compartment (PHC) becomes less prominent, and centromere structure becomes notably enlarged. These epigenetic changes progress slowly after the onset of senescence, with some, such as mobilization of retrotransposable elements becoming prominent only at late times. Many of these changes have also been noted in cancer cells.

【 授权许可】

Unknown   
© 2013 The Authors Aging Cell © 2013 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland