Biology subjects

Vallerga, A.

Publications and source records attributed to Vallerga, A..

2 recordsLinked to original sources

bioRxiv2026

Age-driven miR-29 trades youthful plasticity for epigenetic fidelity

Throughout life, somatic cells must preserve their identity while retaining the capacity to adapt. How this balance shifts with ageing and rejuvenation remains unclear. Here we identify miR-29 as a central point of convergence between the transcriptional programmes of physiological ageing and two routes to rejuvenation: induced reprogramming and the natural reset of early development. miR-29 rises with ageing, falls in both rejuvenation settings and shows the most conserved age-associated increase across vertebrates. miR-29 inhibition opposes transcriptional ageing, whereas mimics promote an older transcriptional state. Methylome analysis reveals a broader function: inhibition releases the miR-29 brake on remodelling, and mimic treatment reinforces it. This release increases methylation at repeat-associated CpGs and lowers epigenetic-clock estimates through unequal contributions in opposite directions. Inhibition also amplifies stimulus-induced methylation changes but reduces fidelity to lineage-specific methylation patterns. We extend this relationship to cancer, where low miR-29 expression marks tumours with younger epigenetic-age estimates yet greater methylation divergence from their tissue of origin. These findings identify miR-29 as a control point linking ageing, rejuvenation and cancer, and support a maladaptive trade-off model in which epigenetic fidelity is preserved at the expense of the plasticity needed for methylome maintenance and adaptation.

cell biology↗

bioRxiv2025

TRIM24 Degradation Counteracts Adaptation to Androgen Receptor Inhibition in Prostate Cancer

The androgen receptor (AR) is the primary therapeutic target in prostate cancer. While androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSi) are effective, the disease eventually progresses to fatal castration-resistant prostate cancer (CRPC). That said, little is known about the mechanisms in residual disease that initiates tumor relapse upon ADT/ARSi. Here, we discover a crucial role for TRIM24 in supporting the survival of residual cell clusters primed for tumor relapse in vivo. Consequently, reducing TRIM24 with bifunctional degraders (dTRIM24) significantly delays or even prevents the emergence of CRPC in the context of AR reactivation and lineage plasticity. dTRIM24 not only inhibits AR signaling but also counteracts adaptive pathways engaged by AR inhibition itself, such as STAT3 activation and EMT. Our findings underscore the potential of TRIM24 as an effective and druggable target for preventing prostate cancer progression under AR inhibition. SignificanceDespite advances in targeting AR signaling in prostate cancer, tumor relapse remains a major concern. Here, we provide evidence that more durable responses can be achieved by pharmacologically degrading TRIM24. At the molecular level, TRIM24 degradation inhibits both AR signaling and adaptive pathways that enable tumor relapse.

cancer biology↗