Hypoxia promotes proliferation of alveolar epithelial cells by regulating chromatin H2A. Z deposition through TAZ-H2A. Z axis

To explore the role and underlying mechanism of the transcriptional coactivator with PDZ-binding motif (TAZ) and a histone variant of acute histone H2A (H2A. Z) in the repair of hypoxia-induced lung injury.

A mouse model of hypoxic lung injury was established by being placed in a hypoxia chamber (simulating an altitude of 5800 m) for 4 d. HE staining was used to observe the severity of lung injury. A hypoxia model of murine alveolar epithelial cells (murine lung epithelial-12, MLE12) was constructed by treating the cells in a hypoxia workstation (1%O₂ concentration) for 24 h. Western blotting was employed to detect TAZ expression. The proliferation of alveolar epithelial cells (AECs) was evaluated by CCK-8 assay. Co-immunoprecipitation (Co-IP) assay was utilized to verify the interaction between TAZ and H2A. Z. CUT&Tag sequencing was performed to determine the effect of TAZ on the chromatin deposition of H2A. Z.

Hypoxia significantly induced alveolar atrophy and inflammatory infiltration in mouse lung tissues (P<0.01). Hypoxia significantly up-regulated the protein level of TAZ in MLE12 cells (P<0.05). CCK-8 assay showed that knockdown of TAZ significantly reduced the proliferative capacity of AECs (P<0.01). Co-IP assay confirmed the physical interaction between TAZ and H2A. Z. CUT&Tag sequencing revealed that hypoxia promoted the deposition of H2A. Z on chromatin (31817 peaks under normoxia, 44078 peaks under hypoxia), which was partially reversed by TAZ knockdown (37840 peaks).

Hypoxia significantly up-regulates the expression of TAZ, which combines with H2A. Z and promotes the deposition of H2A. Z on chromatin, thus enhancing the proliferation of AECs in response to hypoxic injury.