Gene Expression

Gene expression programs that establish and maintain specific cell states are controlled by thousands of transcription factors, cofactors, and chromatin regulators. ^[1] Epigenetic modifications including DNA methylation, histone modifications, chromatin remodeling, and RNA modifications regulate the growth, development, and diseases of individuals by affecting chromatin activity and regulating gene expression. ^[2]

Transcriptional co-regulators are essential mediators of transcription factor function, with most co-activators associated with histone acetylation and co-repressors with histone deacetylation, and remodeling of chromatin required before stimulation of RNA polymerase recruitment or release from the promoter. ^[3] Beyond transcription itself, gene expression is regulated post-transcriptionally by microRNAs, small non-coding RNAs that block translational protein synthesis and/or degrade target mRNAs. ^[4] RNA modifications add a further regulatory layer, as m6A demethylation by ALKBH5 controls gene expression by affecting multiple events in RNA metabolism such as pre-mRNA processing, mRNA decay and translation. ^[5]

The accumulation of molecular damage together with modifications in the epigenetic landscape, dysregulation of gene expression, and altered endocrine communication drives the aging process and establishes age as the main risk factor for age-associated diseases. ^[6] Almost all physiological changes of old age are associated with alterations in gene expression, whether causal or consequential, motivating the search for regulatory factors that change chromatin structure and function and ultimately result in deregulated gene expression. ^[7] Single-cell transcriptomic data show aging-related changes in cellular gene expression, including an increased fraction of cells expressing the senescence marker p16 (CDKN2A) and, in many studies, an increase in transcriptional heterogeneity with age. ^[8]

Misregulation of gene expression programs can cause a broad range of diseases, and advances in understanding transcriptional regulation have provided new insights into transcriptional misregulation in disease. ^[1] Because epigenetic modifications are reversible, specific epigenetic inhibitors targeting epigenetic changes are useful in disease therapy. ^[2] Oligonucleotides can be used to modulate gene expression via processes including RNAi, RNase H-mediated target degradation, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing, with several oligonucleotide drugs recently gaining approval. ^[9] Gene expression databases such as GenAge, LongevityMap and CellAge have been mined to identify genes regulated in aging, longevity, and age-related diseases as candidate biomarkers of frailty. ^[10]