Dissecting FOXO-mediated Transcription Noise to Stall Cellular Dysfunction in Ageing

Ageing is the result of accumulated cellular dysfunction and loss of tissue homeostasis, which often leads to the emergence of age-related pathologies such as cancer and cardiovascular disorders. The disruption of tissue homeostasis during ageing is particularly critical in the case of the vascular endothelium.

The signaling interface and barrier to external factors is provided by a single layer of endothelial cells in a quiescent state.

The maintenance of this quiescent state plays an important role in vascular aging and development of cardiovascular diseases.

Previous studies have shown that the FOXO1 is a critical driver of endothelial quiescence, where its loss and overexpression leads to vascular overgrowth and rarefaction, respectively.

My preliminary analyses show that gene expression levels of FOXO family varies in aged-tissues and that FOXO1/3/4 mutant mice display significant vascular malformation in the retina.

On the other hand, ageing is associated with an increase of transcriptional noise and accumulation of aberrant RNA, which if not eliminated, may lead to cellular dysfunction.

My preliminary data shows that even healthy tissues have significant levels of transcriptional noise, while old individuals present higher levels of such aberrant transcription. However, transcription noise is an unexplored phenomenon impacting cell homeostasis.

In addition, my analyses also show that FOXO1 overexpression in cultured human endothelial cells leads to higher levels of transcription noise.

Given the accumulating evidence and my preliminary findings, I propose to explore how the dysregulation of FOXO transcription factors increases transcription noise, promoting functional decline of the vascular endothelium through ageing.

Understanding the cascade events that drive this transcription aberrancy can have a significant impact on the prevention of cellular function decline and delay a wide range of ageing illnesses.