As cracks to walls and beams can lead to an old house coming apart at the seams, the architectural alterations associated within an aging nucleus can prompt degenerative processes at the cell and tissue level. While any good architect can identify and help to sure up the problematic elements bringing down the house, the blueprints of cellular aging have so far remained elusive.
As inactive genes that lack CpG islands lie within nuclear lamina-associated heterochromatin, researchers led by Samuel Beck (MDI Biological Laboratory, Bar Harbor, ME, USA) sought to explore a possible link between their altered expression due to nuclear architecture alterations and aging. Excitingly, the team now reports that architectural woes prompt age-related problems thanks to the upregulated expression of genes lacking CpG islands.
So, let’s get the hard hats and hi-vis vests on and look over the blueprints of this new study from Lee and colleagues:
- Evaluations of mouse models of normal and pathological aging and meta-analyses of published human and mouse data revealed global overexpression of genes lacking CpG islands in aged cells and tissues
- Lower levels of the nuclear lamina component lamin B1, the inner nuclear membrane protein lamin B receptor, and heterochromatin protein HP1α provide evidence that disorganized nuclear architecture and associated heterochromatin domains drive the overexpression of genes lacking CpG islands during aging
- Overexpression occurs for genes lacking CpG islands from heterochromatic and euchromatic regions, with the latter due to an increased susceptibility to uncontrolled transcription factor-mediated activation in aged nuclei with decondensed heterochromatin
- The dysregulated expression of genes lacking CpG islands prompts age-related physiological deterioration by impacting established hallmarks of aging, including the increased secretion of inflammatory mediators (associated with the senescence-associated secretory phenotype or SASP) and the disruption of intercellular communication
- Aged tissues in mouse models with disrupted nuclear architectures and senescent cells share the expression of proinflammatory secretory genes that lack CpG islands (“inflammaging”)
- Genes lacking CpG islands also encode for most proteins overexpressed in aged plasma
The authors of this architectural wonder of a study also suggest that the missexpression of genes lacking CpG islands may foster other changes observed in aged cells, such as the global loss of functional identity and increased transcriptional noise, and so, may serve as a valuable, novel biomarker of physiological aging. Furthermore, additional explorations into links between the dysregulated genes lacking CpG islands and age-associated diseases may provide insight into pathogenesis and identify potential therapeutic targets.
For more details on this architectural gem, put your hard hat on and read the blueprints at Science Advances, December 2021.