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Review
. 2018 Sep;19(6):464-482.
doi: 10.2174/1389202919666180503125850.

Regulation of Age-related Decline by Transcription Factors and Their Crosstalk With the Epigenome

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Free PMC article
Review

Regulation of Age-related Decline by Transcription Factors and Their Crosstalk With the Epigenome

Xin Zhou et al. Curr Genomics. .
Free PMC article

Abstract

Aging is a complex phenomenon, where damage accumulation, increasing deregulation of biological pathways, and loss of cellular homeostasis lead to the decline of organismal functions over time. Interestingly, aging is not entirely a stochastic process and progressing at a constant rate, but it is subject to extensive regulation, in the hands of an elaborate and highly interconnected signaling network. This network can integrate a variety of aging-regulatory stimuli, i.e. fertility, nutrient availability, or diverse stresses, and relay them via signaling cascades into gene regulatory events - mostly of genes that confer stress resistance and thus help protect from damage accumulation and homeostasis loss. Transcription factors have long been perceived as the pivotal nodes in this network. Yet, it is well known that the epigenome substantially influences eukaryotic gene regulation, too. A growing body of work has recently underscored the importance of the epigenome also during aging, where it not only undergoes drastic age-dependent changes but also actively influences the aging process. In this review, we introduce the major signaling pathways that regulate age-related decline and discuss the synergy between transcriptional regulation and the epigenetic landscape.

Keywords: Aging; Chromatin remodeling; Epigenetics; Lifespan; Stress response; Transcripton.

Figures

Fig. (1)
Fig. (1)
Overview of the major aging-regulatory signaling pathways and their downstream transcription factors, relaying distress signals into aging-preventive transcriptional responses. The various pathways and transcription factors shown are mentioned in the section of ‘transcription factors as central components of aging regulatory signaling pathways’.
Fig. (2)
Fig. (2)
Examples of functional interactions between transcription factors and the epigenome in aging regulation. The ability of transcription factors to bind their target promoters is profoundly influenced by the promoters’ accessibility, which in turn is dictated by its epigenetic state. a) For instance, DNA hypermethylation in promoter regions prevents binding of the DNA-methylation-sensitive transcription factor NRF1. b) On the level of nuclear organization, silenced chromatin is often anchored to the nuclear lamina and acquires repressive histone marks like H3K9me2, forming lamina-associated domains (LADs). Such structure ensures proper gene silencing. However, in progeria, defects in the nuclear lamina severely disrupt the genomic organization, hence causing aberrant global gene expression and premature aging. c) While succumbed to epigenetic states, transcription factors can also actively shape the epigenome as a means to confer transcriptional effects. The FOXO transcription factors serve as good examples. In C. elegans, FOXO/DAF-16 is able to access even repressed chromatin regions and convert them to a more accessible state by recruiting the chromatin remodeler SWI/SNF which repositions the nucleosomes, presumably enabling binding of the transcription machinery. d) At genomic loci with open chromatin and active histone marks, FOXO3 may bind and recruit histone modifiers to further reinforce this activated epigenetic state and thus promote transcription.

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