Functional genomics of ageing: implications of chromatin landscape and beyond

Ageing is an inevitable process of life that is characterised by progressive functional decline of cells, tissues and organs. This ageing process is also accompanied by increased susceptibility to various pathologies such as cancer, metabolic diseases, cardiovascular and neurodegenerative disorders [1]. Therefore, understanding ageing at the molecular level could provide insights for intervening strategies with the aim to delay this process and improve human health. In a seminal publication by Lopez-Otin et al. in 2013, nine hallmarks of ageing were described which represent traits and mechanisms of ageing shared across different organisms [2]. Notably, many of these ageing hallmarks, like genomic instability, telomere attrition, epigenetic alterations, stem cell exhaustion and cellular senescence, are interconnected and the chromatin landscape serves as the intersection among these hallmarks.

The rapid advances in next-generation sequencing technologies have let to the development of multi-omic approaches which facilitate the study of the chromatin landscape [3], and thereby its consequential effects on DNA-related processes such as transcription, repair and replication. These innovative approaches are currently being applied in ageing research and have become imperative for establishing how the chromatin landscape changes during ageing in individual cells. It is becoming apparent that alterations of this chromatin landscape, including changes in histone and DNA modifications, 3D genome organisation and DNA accessibility, are associated with the ageing process and rejuvenating this chromatin landscape could be a prime target in interventions that aim to promote healthy ageing and longevity [4–8]. In this special issue of Briefings in Functional Genomics, a new generation of experts working at the interface of the fields of chromatin biology and ageing provide an overview on the current state of knowledge relating to models and approaches used to functionally characterise genomic components implicated in ageing, the impact of age-related chromatin and transcriptome changes, and opportunities to exploit this knowledge in order to extend healthspan.

The opening review by Legon and Rallis introduces the unicellular yeasts, Saccharomyces cerevisiae and Schizosaccharomyces pombe, as ideal models for high-throughput genome-wide screening to identify and characterise ageing-related genes and their corresponding networks. Specific focus is given on screens for deciphering mechanisms of chronological ageing, which reflects the time that a post-mitotic cell population is viable. For some of these screens, microarrays or, more recently, barcode sequencing technologies have been developed to facilitate those investigations. The authors also describe how these genetic screens are being combined with chemical compounds and/or performed under different cellular conditions (i.e. nutrient deprivation or enrichment) to further scrutinise ageing-associated genetic networks. Finally, they summarise computational tools that have been developed to enable efficient analysis of yeast chronological lifespan screens [9].

Genetic components implicated in human ageing are either deduced from screens in model organisms like the ones described above, or often identified through genome-wide association studies (GWAS) [10]. Although many genetic variants are identified from GWAS, it remains important to validate their functional impact on ageing. Accordingly, in their review, Deelen and colleagues propose a research pipeline for the mechanistic characterisation of human ageing-associated genetic variants. The proposed pipeline entails a series of interconnected steps including in silico characterisation using different computational methods followed by in vitro studies in cell-based models and finally by in vivo characterisation using animal models. The authors also take the opportunity to provide an overview of animal models commonly used in ageing research and specifically in genetic studies, highlighting their advantages and limitations [11].

One ageing hallmark that has been linked to alterations in the chromatin landscape is cellular senescence. In their review, Neretti and colleagues describe various changes in chromatin and nuclear organisation in general which trigger an irreversible cell-cycle arrest that is characteristic of senescent cells. The authors first focus on the contribution of heterochromatin remodelling, histone modifications and histone variants to senescence. They then discuss how remodelling of the nuclear envelope and 3D genome organisation enable the senescent phenotype. Lastly, the authors summarise how regions rich in repetitive DNA sequences such as telomeres, centromeres and transposons, which make up a significant fraction of the eukaryotic genome, are reordered during cellular senescence [12].

Another hallmark of ageing that has been linked to chromatin landscape changes is stem cell exhaustion, which is characterised by age-associated deficiency in stem cells and a consequential decline in tissue regeneration. The review by Pouikli and Tessarz initially provides an overview of chromatin-mediated regulation of stem cell fates and then focuses on the current state of knowledge relating to age-dependent changes of the epigenome that impact stem cell activity. The authors not only highlight studies which investigated DNA methylation and histone modifications changes in ageing stem cells, but also suggest that integrating these investigations with analysis of chromatin architecture and associated transcriptional outputs will provide functional and mechanistic insights into the role of the epigenome during stem-cell ageing. They conclude their review by discussing the potential of manipulating the chromatin landscape as a tool to impede age-related decline of stem cell function [13].

A prominent hallmark of ageing is the progressive failure of the immune system known as ‘immunosenescence’, which is also associated with a low-grade chronic inflammation, a phenomenon termed ‘inflamm-ageing’ [14]. Benayoun and colleagues focus their review on these phenomena and provide an overview for the various innate immune cell types that are key contributors to age-related inflammation. For each described immune cell-type, the authors present evidence showing that age-related changes of the transcriptional landscape within these cells culminate in specific functional deficiencies like, reduced phagocytic capacity, dysregulation of cytokine production and defects in antigen-presentation ability. Moreover, the authors highlight the need for future functional genomic studies that will decipher how pro-longevity interventions and biological sex may impact age-related immune cell dysfunction [15].

The closing review of this special issue by McCauley and Dang provides an overview on the role of the interesting phenomenon of cryptic transcription in mammalian ageing. Although this phenomenon, which is characterised by dysregulated transcription initiating from intragenic regions producing aberrant transcripts, has been previously detected in yeast and has been linked to ageing [16], its relevance to mammalian ageing remains unclear. The authors discuss findings from studies which show that aged chromatin landscapes lead to a permissive state for cryptic transcription especially in stem cells and allude to cellular processes through which cryptic transcription may contribute to mammalian ageing [17].

It is now well accepted that alterations in genome and chromatin regulation are intricately linked to the hallmarks of ageing but understanding the causality between these changes and the ageing process is an active area of investigation. This special issue attempts to provide readers with recent advancements within this area of research through reviews covering a wide range of topics, experimental models and functional genomic approaches used in ageing studies. Importantly, studies such as the ones discussed in these reviews will potentially pave the way towards healthy ageing.

Acknowledgements

I would like to thank all authors and anonymous reviewers for their valuable contributions towards this special issue. I would also like to thank Dr Alison Bentley from the Briefings Editorial Office for her support and guidance.

Funding

Work in the A.K. laboratory is supported by grants from the Cyprus Research and Innovation Foundation (Excellence: 0918/0081, 0918/0105, 1216/0036 and 1216/0215) and the Cyprus Cancer Research Institute (CCRI-2020-FUN-001-103).