Oral Presentation 47th Lorne Genome Conference 2026

Deterministic principles and global chromatin organisation of ageing mammalian cochlea. (133526)

Kenta Ninomiya 1 , Elena Chrysostomou 2 , Joseph Rhodenhiser 2 , Cayla Miller 2 , Lauren Sullivan 2 , Tatyana Sharpee 3 , Uri Manor 2 , Alexey V Terskikh 1
  1. Harry Perkins Institute, Nedlands, WA, Australia
  2. University of California San Diego, San Diego, CA, USA
  3. Salk Institute for Biological Studies, San Diego, CA, USA

Accurate assessment of cell identity and function is a key question in biology. Current single-cell sequencing suffers from incomplete mRNA capture (the dropout phenomenon). Indeed, pseudo-bulking/spatial smoothing is needed for mechanistic analyses. The spatial organisation of the chromatin states and epigenome in the nucleus determines cell identity and function, including age-related changes. However, achieving a single-cell accuracy remains a major challenge. We developed a co-ordination of chromatin determinants (CODE) tensor, a computational framework that transforms 3-dimensional confocal microscopy images into a spatially invariant quantitative signature of the chromatin and epigenetic landscape. We employed CODE tensor to investigate the spatiotemporal characteristics of inner hair cells (IHCs), which play a key role in hearing and its age-related decline in the mouse cochlea. We captured IHC’s identity with 0.97 accuracy, including de novo analysis of SAMP8 mice, whose IHCs appear to age faster. Remarkably, we discovered a “gradient” of epigenetic changes in IHCs that can predict IHC position along the tonotopic axis of the mouse cochlea. We trained a model to distinguish IHCs by frequency (function) and age, achieving over 0.94 single-cell accuracy. We discovered that while IHCs' identity could be accurately defined by a few salient features, age-related changes in IHCs are spatially distributed. Yet, the most salient nuclear features of ageing are linked to the spread of H3K27ac mark and the loss of spatial coordination between H3K27me3 and H3K27ac marks. Finally, we discovered that IHC function, as determined by auditory brain stem recording, is best correlated with a linear combination of IHC loss, epigenetic gradient score, and chromatin and epigenetic age (ImAge), suggesting that distinct individual epigenetic age-related changes may precede the hearing loss. It will be important to test this framework in other organs and tissues to determine whether individual age-related chromatin and epigenetic changes underpin functional decline.