Research Article: Age-associated bimodal transcriptional drift reduces intergenic disparities in transcription

Date Published: April 27, 2018

Publisher: Impact Journals

Author(s): Byungkuk Min, Myungsun Park, Kyuheum Jeon, Jung Sun Park, Hyemyung Seo, Sangkyun Jeong, Yong-Kook Kang.

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Abstract

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. We examined 285 exonic sequences of 175 genes using targeted PCR sequencing in skeletal muscle, brain, and splenic CD4+ T cells of wild-type and HD mice. 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 relationship 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.

Partial Text

Aging is a multifactorial process during which molecular alterations such as genetic and epigenetic mutations accumulate, resulting in decrepitude, frailty, and untimely death. Aging is of significant importance for human health because it is the primary risk factor for a variety of diseases including cancer, metabolic disorders, and neurodegenerative diseases [1–4]. Great strides have recently been made by studies that have led to a systematic categorization of the molecular hallmarks of aging [5]. These individual traits interact with the transcriptional network, which directly influences the transcriptomic profile. Therefore, the exploration of age-associated features of gene expression is fundamental for elucidating the mechanisms underlying the deteriorated cellular functions observed during aging and in age-related disorders. Transcriptomic signatures of aging have indeed been reported for a number of species and tissues (for review, see [6]). These massive scale studies have mostly aimed at detecting either tissue specific or tissue independent aging marker genes that show statistically significant age related changes in expression levels, but a few have been interested in identifying the patterns of transcriptional drift of individual genes and the elements that decide the pattern.

As demonstrated in Fig. 1C, old T cells unambiguously showed A3GE that was markedly aggravated in the HD genotype. In support of this result, previous studies have observed that there was a substantial change in mRNA expression in the blood of HD patients [13,22–24]. Moreover, the T cell A3GE was distinguished by the opposing patterns of transcriptional drift – the upregulation of the low expression level genes and the downregulation of the high expression level genes (Fig. 4A). This convergence reduces the difference in expression levels between low and high transcription activity genes, suggesting a progressive loss of discrimination in the regulation of gene expression with age. Given that aging is accompanied by changes in chromatin structure [6,25], this bidirectional A3GE may be explained by the age-associated perturbation of epigenomic structure such as loss of nucleosome occupancy and subsequent increase of chromatin opening [26,27]. These changes increase transcriptional noises among barely expressed genes, probably in a stochastic fashion [28], which consequently appropriate cellular resources for transcription. This individually tiny (at the level of individual genes), but collectively immense, pan-genome increase in transcription may cause a scarcity of nuclear resource for the transcription of major expressing genes. This scenario assumes a re-distribution of transcriptional resource from the majorly expressed genes to the minimally expressed genes with age.

 

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