Control of transcription in aging WI38 cells stimulated by serum to divide

Abstract

In the present work, age-related alterations in histone acetylation and in the enzymatic system responsible for acetylation were examined in two growth states of WI38 fibroblasts. These observations were correlated with transcriptional activity of the cells when quiescent and after stimulation by serum to divide. In young WI38 cells (less than 50% lifespan completed), application of a growth stimulus resulted in sustained increase in transcription occurring after serum stimulation. However, senescent cultures (greater than 80% lifespan completed), while exhibiting 3-fold greater basal levels of transcription when quiescent, showed only 50% as great an increase in transcription following serum stimulation. Turnover of labile histone acetate was observed to decrease following stimulation of young cultures, but in senescent cultures, little turnover was evident either before or after stimulation. Examination of histone acetylase and deacetylase activity in isolated nuclei revealed that deacetylase activity was markedly altered between the resting and growing state and also with age. In resting young cells, two rates of deacetylase activity were apparent, but stimulated cells exhibited only one rate. In addition, at the end of the reaction period, resting cells had removed twice as much incorporated [ 14C]acetate as had stimulated cells. In contrast, both stimulated and quiescent senescent fibroblasts exhibited two rates of deacetylation, but little deacetylase activity was apparent in either case. The present studies demonstrate an inverse correlation between rates of RNA synthesis and turnover of histone acetate. Enzymatic studies suggest that this result is due to a decrease in histone deacetylase activity.