Multi-omics analyses revealed H1.2 is the modulator of cellular adaptation to hypoxia and cancer resistant in naked mole rats

The naked mole rat (NMR, Heterocephalus glaber) is the known longest-living rodent species, and is extraordinarily resistant to hypoxia, cancer and aging-related diseases. Here, to explore the cellular response to hypoxia in NMR, NMR embryonic fibroblast cells (NEFs) and mouse embryonic fibroblast cells (MEFs) were first exposed to anoxia for 1, 2, 3 and 4 hours, and a combination of comparative ATAC-seq, transcriptomics and proteomics was employed to explore differentially expressed genes. Comparative protomics reveals H1.2 (HIST1H1C) show accumulated difference between NEFs and MEFs. Mechanistic studies then identified that high expression of H1.2 in NEFs was associated with low expression its inhibitor PARP1. Co-immunoprecipitation and truncation assay revealed that H1.2 directly interacted with HIF-1α PAS domains. And, we found overexpression of H1.2 could induce autophagy and expression of HIF1α, and knock down of H1.2 decreases autophagy and HIF-1α expression. Furthermore, we also found that overexpression of H1.2 can inhibit migration of cancer cells and xenograft tumor formation, most likely through autophagy. Finally, H1.2 knock-in mouse model was constructed and they shown prolonged hypoxic survival time. Taken together, these findings suggested H1.2 involves the crosstalk between hypoxic adaptation and cancer resistant in naked mole rats.