Oral Presentation 46th Lorne Genome Conference 2025

Imaging-based chromatin and epigenetic age. (115047)

Kenta Ninomiya 1 , Alexey Terskikh 2
  1. University of Western Australia, Perth
  2. The Scintillon Research Institute, San Diego

Recently, we described imaging-based chromatin and epigenetic age (ImAge), which captures intrinsic age-related progressions of the spatial organization of chromatin and epigenetics in single nuclei. Such trajectories readily emerge as principal changes in each individual dataset. We find that interventions known to affect biological aging induce corresponding effects on ImAge, including increased ImAge upon chemotherapy treatment and decreased ImAge upon caloric restriction and partial reprogramming by transient OSKM expression in liver and skeletal muscle. Further, ImAge readouts from chronologically identical mice inversely correlated with their locomotor activity, suggesting that ImAge may capture elements of biological and functional age. ImAge represents the first-in-class imaging-based biomarker of aging (Alvarez-Kuglen et al., Nature Aging 2024). Currently, profiling epigenetic age in single cells uses dissociated cells. However, a key aspect of tissue aging is the 3-dimensional spatial organization of different cell types in tissues. It is essential to develop accurate and robust approaches to quantitate epigenetic states in single cells in situ. We propose mammalian cochlea as a new and unique model to study aging in situ. Inner hair cells (IHC) are arranged in a strict anatomically defined order along a tonotopic axis from the base (high frequency) to the apex (low frequency) of the mouse cochlea. The location-specific function of IHC can be determined in vivo by recordings at specific frequencies and sound levels. We discovered robust epigenetic changes in IHC with age that could be measured at a single-cell level with high accuracy. We observed a gradient of epigenetic changes along the tonotopic axis, which decreased with age. We will discuss age-dependent single-cell spatial heterogeneity of the epigenetic state in IHC. This imaging-based approach will complement the current methods to investigate the structure and function of chromatin and epigenetics.