Summary: Flies lacking the transcription factor Ets21c died far more quickly when exposed to oxidative stress, revealing a molecular switch that influences tissue renewal, stress resilience, and lifespan.
Source: University of Cologne
The survival and fitness of multicellular organisms depend on their ability to renew tissues throughout life. This renewal is critical in tissues constantly exposed to environmental challenges, such as the intestinal epithelium, which lines the digestive tract. Researchers led by Professor Dr. Mirka Uhlirova at CECAD, the Cluster of Excellence for Aging Research at the University of Cologne, together with Dr. Tony Southall’s laboratory at Imperial College London, identified the transcription factor Ets21c as a key regulator of regenerative processes in the adult intestine of the fruit fly Drosophila. Their work also uncovers a trade-off between stress tolerance and longevity. The findings are published in Cell Reports.
The intestinal epithelium not only absorbs nutrients and supports digestion, it also forms a protective barrier that limits the entry of pathogens and toxins. Continuous renewal of this epithelium is carried out by intestinal stem cells that divide and differentiate to replace aged or damaged cells and preserve tissue integrity. When stem cell activity is disrupted, tissues can degenerate or develop cancer. The new study sheds light on the molecular mechanisms that control intestinal regeneration under both healthy and stressful conditions.
Transcription factors bind DNA and control which genes are expressed. Ets21c is a stress-inducible transcription factor that becomes upregulated during bacterial infection, oxidative stress, and aging. Until now, the biological role of Ets21c induction was unclear. Dr. Juliane Mundorf and colleagues used the genetic advantages of the Drosophila model to switch off Ets21c globally or selectively in either intestinal stem cells or differentiated epithelial cells. Surprisingly, flies lacking Ets21c developed normally and, under non-stressed laboratory conditions, lived longer than control flies. This indicates that reducing certain regenerative signals can slow aging under calm conditions.
However, the protective effect reversed under stress. When mutant flies without Ets21c were exposed to an herbicide that generates damaging reactive oxygen species, they died far more rapidly than controls. Experiments localized the critical requirement for Ets21c to the adult intestine: without Ets21c, the gut could not mount the regenerative response needed to survive oxidative damage. In other words, Ets21c is essential for stress-induced regeneration but may be dispensable for development and even limit lifespan when active chronically.
Using a combination of targeted genetics and genome-wide transcriptional profiling, the team demonstrated that Ets21c controls distinct gene programs in different cell types. In intestinal stem cells, Ets21c promotes proliferation to replace lost cells. In mature enterocytes, Ets21c helps trigger apoptosis and removal of damaged cells, coordinating their elimination with stem cell-driven replacement. This dual role ensures balanced epithelial turnover: enough regeneration to repair damage, but not so much that it causes excessive cell proliferation or tissue deterioration.
Crucially, Ets21c activity must be finely tuned. Loss of Ets21c reduces epithelial turnover, a state that can delay age-related tissue decline and extend lifespan in a stable environment. Conversely, overactivation of Ets21c drives accelerated tissue turnover, leading to hyperproliferation, tissue dysfunction, and premature aging. These observations point to a physiological trade-off: robust stress responses that protect against acute damage can come at the cost of accelerated aging when sustained chronically.
Another important aspect of the study is evolutionary conservation. The Ets21c transcription factor belongs to an ETS family whose members and the associated signaling networks are conserved from flies to mammals. This conservation suggests that ETS-type factors and their stress signaling pathways might similarly influence epithelial renewal and stress tolerance in mammalian, possibly human, tissues.
Looking ahead, the researchers plan to investigate how Ets21c levels and activity are regulated under different conditions and whether other tissues besides the intestine rely on Ets21c for maintenance and stress responses. Understanding these control mechanisms could reveal how organisms balance regeneration and longevity and might point toward strategies to improve tissue resilience without accelerating aging.
Source:
University of Cologne
Media contact:
Mirka Uhlirova – University of Cologne
Image source:
The image is in the public domain.
Original research (open access):
“Ets21c Governs Tissue Renewal, Stress Tolerance, and Aging in the Drosophila Intestine.” Juliane Mundorf et al., Cell Reports. DOI: 10.1016/j.celrep.2019.05.025
Abstract highlights
• Ets21c acts downstream of JNK signaling to promote epithelial renewal in the adult intestine.
• Both intestinal stem cell proliferation and apoptosis of enterocytes depend on Ets21c.
• Ets21c controls cell-type-specific gene expression programs.
• Loss of Ets21c can prevent intestinal aging under non-stressful conditions but increases sensitivity to stress.
Summary: Homeostatic renewal and stress-related regeneration depend on coordinated stem cell activity to replace damaged cells and maintain tissue function. JNK signaling is a known regulator of intestinal homeostasis, and this study shows that its effects require the stress-responsive transcription factor Ets21c. Ets21c orchestrates both intrinsic and non-autonomous mechanisms that coordinate proliferation and cell removal. While Ets21c deficiency slows epithelial aging, it compromises the ability of intestinal cells to respond to oxidative stress, positioning Ets21c as a vital regulator of midgut proliferative balance and a determinant of adult healthspan.