Age‐associated increase in heterochromatic marks in murine and primate tissues

Abstract

SummaryChromatin is highly dynamic and subject to extensive remodeling under many physiologic conditions. Changes in chromatin that occur during the aging process are poorly documented and understood in higher organisms, such as mammals. We developed an immunofluorescence assay to quantitatively detect, at the single cell level, changes in the nuclear content of chromatin-associated proteins. We found increased levels of the heterochromatin-associated proteins histone macro H2A (mH2A) and heterochromatin protein 1 beta (HP1b) in human fibroblasts during replicative senescence in culture, and for the first time, an age-associated increase in these heterochromatin marks in several tissues of mice and primates. Mouse lung was characterized by monophasic mH2A expression histograms at both ages, and an increase in mean staining intensity at old age. In the mouse liver, we observed increased age-associated localization of mH2A to regions of pericentromeric heterochromatin. In the skeletal muscle, we found two populations of cells with either low or high mH2A levels. This pattern of expression was similar in mouse and baboon, and showed a clear increase in the proportion of nuclei with high mH2A levels in older animals. The frequencies of cells displaying evidence of increased heterochromatinization are too high to be readily accounted for by replicative or oncogeneinduced cellular senescence, and are prominently found in terminally differentiated, postmitotic tissues that are not conventionally thought to be susceptible to senescence. Our findings distinguish specific chromatin states in individual cells of mammalian tissues, and provide a foundation to investigate further the progressive epigenetic changes that occur during aging.

Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence

“…Our data provide an additional mechanism for transcriptional activation of hTERT during cancer progression in humans-one that may be independent of promoter mutations and that requires cells to first undergo chromatin changes associated with OIS. In line with this interpretation are our observations that hTERT-positive cells in intermediate-and late-stage human breast and melanocytic skin cancers also display high levels of HP1β, a heterochromatin protein whose abundance peaks in senescent cells (31). Because we did not detect any cells that simultaneously displayed high levels of hTERT and low levels of HP1β, our data suggest that cancer cells emerged from HP1β-positive and therefore senescent somatic cells in analyzed lesions.…”

Impaired secretion of interferons by dendritic cells from aged subjects to influenza

“…In contrast, decreased heterochromatin-specific H3K9me3 due to reduced expression of the recruiting protein HP1 has been reported in aged humans (Scaffidi and Misteli 2006). A recent study (Kreiling et al 2011) reported an age-associated increase in heterochromatin marks in several tissues of mice and primates. There is a scarcity of information regarding age-associated changes in chromatin organization changes particularly in human immune cells.…”

Mitochondria in the spotlight of aging and idiopathic pulmonary fibrosis

“…Epigenetic mechanisms are able to modulate gene activity in the absence of DNA sequence changes, including DNA methylation, histone modification, and expression of noncoding RNAs (microRNAs [miRNAs] and long noncoding RNAs [lncRNAs]). Epigenetic changes that are associated with age (33,34) seem to be highly conserved in mammals (35,36), especially the global change of DNA methylation patterns, also known as the "epigenetic clock." This particular loss of methylation and the subtle differences between changes in healthy aging and in age-related pathological processes (37) could be the key to identifying novel biomarkers in IPF, since it exhibits its own particular methylation profile (38).…”