HIRA-mediated H3.3 deposition preserves hepatocyte cell identity during non-proliferative liver aging [CUT&Tag]

Age-associated functional decline is partly driven by progressive chromatin degeneration. Conversely, maintenance of chromatin integrity preserves cell identity and promotes healthy aging, albeit through different mechanisms in proliferating and non-proliferating cells. However, whether tissue regeneration with its associated cell proliferation can rescue defects in epigenetic maintenance in otherwise non-proliferative cells remains unclear. The histone chaperone HIRA deposits the histone variant H3.3 in a DNA replication–independent manner, leading to its accumulation in aging, non-proliferating cells. Here, we show that hepatocyte-specific loss of HIRA causes loss of cell identity, metabolic dysfunction, and accelerated fibrotic pathology with age. Transcriptomic and epigenomic analyses indicate that HIRA–H3.3 preserves chromatin integrity and sustains transcription of highly expressed genes. Partial hepatectomy, associated with induced proliferation, restores cell identity with compensatory deposition of canonical histones H3.1/2. Together, these results demonstrate that HIRA-mediated H3.3 deposition is essential for safeguarding cell identity and tissue function during aging of non-proliferating cells, but this function can be rescued by tissue regeneration with associated cell proliferation.