Is adult stem cell aging driven by conflicting modes of chromatin remodeling?

Abstract

Epigenetic control of gene expression by chromatin remodeling is critical for adult stem cell function. A decline in stem cell function is observed during aging, which is accompanied by changes in the chromatin structure that are currently unexplained. Here, we hypothesize that these epigenetic changes originate from the limited cellular capability to inherit epigenetic information. We suggest that spontaneous loss of histone modification, due to fluctuations over short time scales, gives rise to long-term changes in DNA methylation and, accordingly, in gene expression. These changes are assumed to impair stem cell function and, thus, to contribute to aging. We discuss cell replication as a major source of fluctuations in histone modification patterns. Gene silencing by our proposed mechanism can be interpreted as a manifestation of the conflict between the stem cell plasticity required for tissue regeneration and the permanent silencing of potentially deleterious genomic sequences.