Li, Mengjia;
(2024)
From dFOXO transient activation in youth to extend lifespan by Xbp1: the interplay of transcription factors in determining the pro-longevity transcriptional programme.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The inherent deterioration of a physiological system with time, what we call ageing, is mouldable by numerous interventions across many species. Specifically, transcription factors (TFs) can reprogramme gene expression to promote longevity. In this context, I focus on Drosophila Forkhead box O (dFOXO), an evolutionarily conserved TF known for its role in promoting longevity. The work conducted in the PhD project demonstrated that transient induction of dFOXO solely during early adulthood (dfoxo-switch) significantly enhances both healthspan and lifespan. dfoxo-switch caused persistent chromatin structural alterations in the fat body, accompanied by a long-lasting pro-longevity transcriptional programme that was partially achieved by induction of another TF, X-box binding protein 1 (Xbp1). We identified the chromatin remodellers, SWI/SNF, and ISWI complexes, were required for both Xbp1 induction and the pro-longevity effects of dfoxo-switch. Xbp1 overexpression extended lifespan, which may explain the pro-longevity effect of youth-restricted dFOXO activation. Additionally, I found that dFOXO activation in parents improved the survival of their progeny, unveiling another facet of the dFOXO-induced memory effect. I further explored the role of Xbp1 in the ageing process. Xbp1 is activated by splicing of its primary transcript, Xbp1u, to generate Xbp1s, a key activator of the endoplasmic reticulum unfolded protein response (UPRER). I found that Xbp1s induced the conical UPRER in the gut, promoting longevity from the resident stem cell. In the fat body, Xbp1s triggered a distinct, non-conical metabolic response while still extending lifespan. Remarkably, Xbp1s and dFOXO impinged on the same target genes in the fat body. The extended lifespan resulting from chronic dFOXO activation requires Xbp1, indicating a cooperative relationship between dFOXO and Xbp1 in determining the pro-longevity transcriptional program. Lastly, I present evidence that inducing the poorly characterized Xbp1u also extend lifespan. These findings together illuminated a complex and intriguing TF-TF network that regulates the ageing process.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | From dFOXO transient activation in youth to extend lifespan by Xbp1: the interplay of transcription factors in determining the pro-longevity transcriptional programme |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2024. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | Ageing, Drosophila, FOXO, Transcription factor, Xbp1 |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10196779 |
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