Gene expression profiling in Werner syndrome closely resembles that of normal aging

Abstract

Werner syndrome (WS) is a premature aging disorder, displaying defects in DNA replication, recombination, repair, and transcription. It has been hypothesized that several WS phenotypes are secondary consequences of aberrant gene expression and that a transcription defect may be crucial to the development of the syndrome. We used cDNA microarrays to characterize the expression of 6,912 genes and ESTs across a panel of 15 primary human fibroblast cell lines derived from young donors, old donors, and WS patients. Of the analyzed genes, 6.3% displayed significant differences in expression when either WS or old donor cells were compared with young donor cells. This result demonstrates that the WS transcription defect is specific to certain genes. Transcription alterations in WS were strikingly similar to those in normal aging: 91% of annotated genes displayed similar expression changes in WS and in normal aging, 3% were unique to WS, and 6% were unique to normal aging. We propose that a defect in the transcription of the genes as identified in this study could produce many of the complex clinical features of WS. The remarkable similarity between WS and normal aging suggests that WS causes the acceleration of a normal aging mechanism. This finding supports the use of WS as an aging model and implies that the transcription alterations common to WS and normal aging represent general events in the aging process.W erner syndrome (WS) is an autosomal recessive disease characterized by early onset of many signs of normal aging, such as graying of the hair, scleroderma-like skin changes, ocular cataracts, diabetes, degenerative vascular disease, osteoporosis, and high incidence of some types of cancers (1). As a segmental progeroid syndrome, WS does not exhibit all of the features of normal aging but nevertheless is a very useful model system for the molecular study of normal aging.The molecular basis of WS is a single mutation in the WRN gene, resulting in a truncated WS protein (WRN) characterized by a loss of nuclear localization signal and protein function (2). WRN has been demonstrated to possess helicase and exonuclease activities (3, 4) and belongs to the RecQ family of helicases. Various defects in DNA replication, recombination, repair, and transcription are found in WS fibroblasts (reviewed in ref. 5). The mechanisms by which the biochemical deficiencies resulting from WRN mutations lead to the characteristic pathology of the syndrome are not yet understood. It has been hypothesized that several WS phenotypes are secondary consequences of aberrant gene expression (6) and that a transcription defect may be crucial to the development of the syndrome (7). Increasing evidence suggests that WRN has a role in transcription. Human WRN activates transcription in a yeast system (8), and recent studies from this laboratory demonstrated that RNA polymerase (pol) II transcription is reduced by 40-60% in WS cells, indicating a primary defect in transcription (7). Supporting this finding, we found that RNA pol II transcription i...

Deficient DNA repair in the human progeroid disorder, Werner syndrome

“…The molecular basis of genomic instability in patients with these syndromes is not well understood. Gene expression profiles in WS individuals are similar to those of normal older individuals [3], indicating that WS may be a useful model for normal aging.…”

Creation and implications of a phenome-genome network

“…4b, p = 7.3 × 10 −10 , q < 0.0001); Bdnf has been previously shown to have a significant drop in expression in human skin fibroblasts associated with advancing age. 21 The other nine genes, including Tnnt1, Synj1, Tada2l, Slc7a2, Mgat2, and Kctd2, have no previously established association with aging, though Tnnt1 and Mgat2 have been associated with nemaline myopathy and type 2a congenital disorder of glycosylation, respectively. A decrease in Tnnt1 and an increase in Synj1 have been found to be associated with differentiation from human embryonic and hematopoetic stem cells, respectively.…”

Vitamin C restores healthy aging in a mouse model for Werner syndrome

“…Ascorbate significantly inhibited genes that have been shown to be up-regulated in human WS fibroblasts (38) (Fig. 5B).…”