This study addressed the question of how well the quantitative transcriptome structure established in early life is maintained and how consistently it appears with increasing age, and if there is age-associated alteration of gene expression (A3GE), how much influence the Huntington’s disease (HD) genotype exerts on it. Using a PCRseq-based method, we examined expression profile of 395 exonic segments from 260 “epi-driver” genes in tissues of aged HD mice. We identified 67 exonic segments differentially expressed between young and aged HD mice, most of them upregulated in the aged. Epi-driver gene categories of lysine-methylation, lysine-demethylation, and arginine-methylation showed differential age-associated changes between HD and control. Analyzing the pattern of change in epi-driver gene expressions hinted at an enhanced shift in HD chromatin to a more accessible state with age, which was experimentally demonstrated by DNase-I-hypersensitivity sequencing showing increased chromatin accessibility in HD cells compared to control. Meanwhile, in contrast to the muscle and brain, T cells exhibited large A3GE, suggesting a strong contribution to functional decline of the organism. This A3GE was markedly intensified in age-matched HD T cells, which exhibited accelerated aging as determined by reduced telomere length. Regression analysis suggested that gene expression levels change at a rate of approximately 3% per month with age. We found a bimodal relation in A3GE in T-cells in that weakly expressed genes in young mice were increasingly transcribed in older animals whereas highly expressed genes in the young were decreasingly expressed with age. This bimodal transcriptional drift in the T cell transcriptome data causes the differences in transcription rate between genes to progressively reduce with age. We suggest the global change can potentially relieve chromatin-induced repression of many genes, and the unintended expressions of some detrimental proteins could alter T cell function to a greater degree in aged HD mice.
