A cross-species single-cell kidney epigenome atlas reveals epithelial-dominant aging-like states in disease.

Hyeonsoo Jeong, Blue B Lake, Dinh Diep, Xuwen Li, Qi Yan, Debora L Gisch, Madhurima Kaushal, Stephanie Reinert, Michael T Eadon, Joseph P Gaut, Sanjay Jain, Kun Zhang

San Diego Institute of Science, Altos Labs, San Diego, CA, USA.San Diego Institute of Science, Altos Labs, San Diego, CA, USA. · pubmed

Paper

Abstract

Epigenetic aging is a hallmark of chronic diseases. While such epigenetic changes can arise following tissue injury, the cell types most affected remain largely unknown. Here we built a cross-species single-cell multiomics atlas of DNA methylation, chromatin accessibility and transcription profiles from healthy, injured (human) and aged (mouse) kidneys. We found that tubular epithelial cells in diseased kidneys exhibit pronounced accelerated epigenetic aging and showed that this pathological state mirrors transcriptional trajectories observed during aging, driven by preferential dysregulation of lineage-specific genes lacking CpG islands. Spatially, these epigenetic changes mapped to pathological niches of unresolved repair. Co-profiling single-cell DNA methylation and 3D genome architecture revealed that epithelial repair states in disease undergo significant higher-order genome reorganizations, alongside activation of genes associated with renal decline. Together, our findings characterize a loss of epigenetic repression within coordinated three-dimensional chromatin structures and reduced local methylome integrity, which compromises epithelial cell identity during aging and impedes repair.

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Research summary

The paper claims that tubular epithelial cells in diseased kidneys exhibit accelerated epigenetic aging driven by the loss of epigenetic repression and 3D genome reorganization, which compromises cell identity and impedes repair. This is relevant because it identifies specific epigenetic and structural mechanisms underlying the failure of tissue repair and the progression of aging-like states in chronic disease, offering potential targets for interventions aimed at restoring cellular identity and function rather than just treating symptoms.

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