Mazzoccoli, G. | bioRxiv Science

bioRxiv2026

A multilayered in silico analysis links UHRF1, DNA methylation and developmental chromatin memory to lineage-dependent prognosis in gastric, renal and adrenal cancers

Aberrant DNA methylation is a hallmark of cancer, but its clinical interpretation remains debated. UHRF1, a key epigenetic adaptor for DNA methylation maintenance and chromatin bivalency regulation in embryonic stem cells, is frequently overexpressed yet shows context-dependent prognostic behaviour. By integrating bulk and single-cell transcriptomics, CpG-resolution methylation, developmental chromatin states, immune profiling and clinical outcomes across gastric (STAD), clear-cell renal (KIRC) and adrenal (ACC) carcinomas, we identified a four-class UHRF1-embryonic morphogenesis (UHRF1-EM) framework resolving this paradox. This axis revealed an inverse prognostic pattern: whilst across all three tumours EM-low and EM-high states mark better or worse prognosis, respectively, UHRF1-high levels associate with favourable outcome in STAD (UH-EML), and unfavourable in KIRC and ACC (UH-EMH). The classification proved reproducible and independently prognostic after adjustment for stage and molecular subtypes, outperforming existing classifiers and exceeding pathological stage in KIRC and ACC. Multivariable models incorporating UHRF1-EM yielded uniformly positive {Delta}C-indices. Hypermethylation associated with the UHRF1-EM axis was enriched at ESC bivalent developmental loci (EM and oncofoetal genes), but not at housekeeping cell-cycle sites. In STAD, this pattern was related to oncofoetal gene downregulation and best prognosis, whereas in KIRC and ACC it matched with gene-body/enhancer methylation, higher EM expression, immunosuppressive microenvironments and worst prognosis. Together, these findings establish the UHRF1-EM axis as a clinically robust molecular classifier and support a mechanistic model in which tumour-specific epigenetic engagement of developmental loci may contribute to the prognostic inversion, providing a foundation for further mechanistic experimental validation.

cancer biology↗

bioRxiv2018

Systematic analysis of mouse genome reveals distinct evolutionary and functional properties among circadian and ultradian genes

In living organisms, biological clocks regulate 24 h (circadian) molecular, physiological, and behavioral rhythms to maintain homeostasis and synchrony with predictable environmental changes. Harmonics of these circadian rhythms having periods of 8 hours and 12 hours (ultradian) have been documented in several species. In mouse liver, harmonics of the 24-hour period of gene transcription hallmarked genes oscillating with a frequency two or three times faster than the circadian circuitry. Many of these harmonic transcripts enriched pathways regulating responses to environmental stress and coinciding preferentially with subjective dawn and dusk. We hypothesized that these stress anticipatory genes would be more evolutionarily conserved than background circadian and non-circadian genes. To investigate this issue, we performed broad computational analyses of genes/proteins oscillating at different frequency ranges across several species and showed that ultradian genes/proteins, especially those oscillating with a 12-hour periodicity, are more likely to be of ancient origin and essential in mice. In summary, our results show that genes with ultradian transcriptional patterns are more likely to be phylogenetically conserved and associated with the primeval and inevitable dawn/dusk transitions.

bioinformatics↗