Abstract
Dysregulation of gene expression is a hallmark of aging. We examined epigenetic mechanisms that mediate aberrant expression of laminin genes in aging rat kidneys. In old animals, no alterations were found in the levels of abundant laminin mRNAs, whereas Lama3, b3, and c2 transcripts were increased compared to young animals. Lamc2 showed the strongest changes at the mRNA and protein levels. Lamc2 upregulation was transcriptional, as indicated by the elevated RNA polymerase II density at the gene. Furthermore, aging is associated with the loss of H3K27m3 and 5mC silencing modifications at the Lamc2 gene. Western blot analysis revealed no changes in cellular levels of H3K27m3 and cognate enzyme Ezh2 in old kidneys. Thus, the decrease in H3K27m3 at Lamc2 resulted from the re-distribution of this mark among genomic sites. Studies in kidney cells in vitro showed that reducing H3K27m3 density with Ezh2 inhibitor had no effect on Lamc2 expression, suggesting that this modification plays little role in gene upregulation in aging kidney. In contrast, treatment with DNA methylation inhibitor 2'-deoxy-5-azacytidine was sufficient to upregulate Lamc2 gene. We suggest that the loss of 5mC at silenced laminin genes drives their de-repression during aging, contributing to the age-related decline in renal function.
Highlights
In organisms as diverse as yeast and humans, agerelated changes in chromatin structure contribute to alterations in gene expression and progression to aging phenotypes [1]
To distinguish between common versus genotypespecific changes in laminin gene expression during aging, we used F344 and FBN-F1 rat lines, two established model systems supported by the National Institute of Aging (NIA)
Laminin genes expressed at very low levels in young animals – Lama3, b3, and c2 – were induced in old animals, with the largest changes seen in www.aging‐us.com the Lamc2 transcript
Summary
In organisms as diverse as yeast and humans, agerelated changes in chromatin structure contribute to alterations in gene expression and progression to aging phenotypes [1]. One of the hallmarks of aging kidneys is the aberrant accumulation of ECM proteins in the interstitium (interstitial fibrosis) [5, 6]. These alterations contribute to the age-related decline of kidney function, culminating in the organism’s death. We have shown that, during aging, transcription of the ECM gene Col3a1 is increased in rat kidneys, a finding associated with aberrant accumulation of collagen III protein in the interstitium [7]
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