The Epigenetic Profile of Werner Syndrome is Very Different from that of Aging

The research community has long used progeroid syndromes such as Hutchinson-Gilford progeria syndrome and Werner syndrome as tools in the investigation of aging. This category of conditions are colloquially thought of as accelerated aging, but are in fact only a little similar to aging. The various underling genetic causes of progeria result in accelerated accumulation of cellular damage of various sorts, different in each case, leading to tissue dysfunction and outcomes that resemble a range of normal age-related conditions. Aging is itself a process of damage accumulation, so it isn't surprising to find some degree of similarity. The forms of cellular damage and their proportions are quite different, however, which makes it challenging to draw any specific lesson from progeroid syndromes and apply it to normal aging.

Werner syndrome (WRN) is a canonical member of a family of genetically determined disorders that include multiple phenotypes consistent with their characterizations as segmental progeroid syndromes. It is important to note, however, that these syndromes may include discordances with the usual phenotypic features of aging. For example, the ratio of epithelial to non-epithelial cancers in WRN is 1:1, whereas the ratio seen in usual aging is 10:1. Moreover, while WRN research has contributed to the widespread acceptance of genomic instability as one of the hallmarks of aging, features such as variegated translocation mosaicism and a preponderance of large deletions are particularly characteristic of WRN.

Epigenetic signatures of Werner syndrome occur early in life and are distinct from normal epigenetic aging processes. The vast majority (more than 90%) of differentially methylated CpGs and regions (DMRs) in WRN were not affected by aging, consistent with the view that WRN is not merely accelerated normal aging. A particularly striking finding was that DMRs were enriched in genes associated with transcription factor activity, leading us to hypothesize that WRN might best be conceptualized as a disease based upon aberrant controls of the expressions of a wide array of genetic loci, some of which are plausibly related to clinical phenotypes of WRN. Moreover, given that the methylation changes in the highest ranking DMR in the promoter region of the HOXA4 gene as well as in other DMRs preceded disease manifestation, it seems likely that these transcriptional aberrations began early in development. That finding reinforces the concept that how well one builds an organism makes a great deal of difference on how long it lasts and how well it functions!

The epigenome of an individual is most plastic during early development and is shaped by a plethora of stochastic, internal (i.e. genetic variation), and external factors (i.e. environmental exposures). The epigenetic changes associated with WRN and other segmental progerias are widespread but are all of small effect size. Both premature and normal aging phenotypes may manifest when the adverse factors exceed a critical threshold. Individuals with WRN may be endowed with an epigenome early in life which lowers their threshold for developing a number of specific aging phenotype.


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