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

LIU Paiyu; ZHANG Mengjie; ZENG Jitao; NI Bing

doi:10.16016/j.2097-0927.202502051

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

Military Medicine | 更新时间：2025-03-28

- Hypoxia promotes proliferation of alveolar epithelial cells by regulating chromatin H2A.Z deposition through TAZ-H2A.Z axis
- Journal of Army Medical University Vol. 47, Issue 6, Pages: 498-505(2025)
- 作者机构：
  
  1.陆军军医大学（第三军医大学）高原军事医学系病理生理学教研室，重庆
  2.中国人民解放军联勤保障部队第991医院精神心理科，湖北襄阳
  3.陆军军医大学（第三军医大学）第一附属医院生殖医学中心，重庆
- 作者简介：
  
  NI Bing， E-mail： nibing@tmmu.edu.cn
- 基金信息：
  
  the General Project of Natural Science Foundation of Chongqing(CSTB2024NSCQ-MSX0838)
- DOI：10.16016/j.2097-0927.202502051
  CLC： R322.35;R363.125;R364.3
- Received：17 February 2025，
  
  Revised：04 March 2025，
  
  Published：30 March 2025
- 稿件说明：
移动端阅览
刘派予，张梦洁，曾继涛，等.缺氧通过TAZ-H2A.Z轴调控H2A.Z染色质沉积促进肺泡上皮细胞增殖的研究［J］.陆军军医大学学报，2025，47（06）：498-505.DOI：10.16016/j.2097-0927.202502051.

LIU P Y，ZHANG M J，ZENG J T，et al.Hypoxia promotes proliferation of alveolar epithelial cells by regulating chromatin H2A.Z deposition through TAZ-H2A.Z axis［J］.J Army Med Univ，2025，47（06）：498-505.DOI：10.16016/j.2097-0927.202502051.
刘派予，张梦洁，曾继涛，等.缺氧通过TAZ-H2A.Z轴调控H2A.Z染色质沉积促进肺泡上皮细胞增殖的研究［J］.陆军军医大学学报，2025，47（06）：498-505.DOI：10.16016/j.2097-0927.202502051. DOI：

LIU P Y，ZHANG M J，ZENG J T，et al.Hypoxia promotes proliferation of alveolar epithelial cells by regulating chromatin H2A.Z deposition through TAZ-H2A.Z axis［J］.J Army Med Univ，2025，47（06）：498-505.DOI：10.16016/j.2097-0927.202502051. DOI：

摘要

目的

本研究旨在探讨转录共激活因子（transcriptional coactivator with PDZ-binding motif， TAZ）与组蛋白H2A（histone H2A，H2A）的一种组蛋白变体H2A.Z，在缺氧诱导的肺损伤后修复中的作用及其潜在机制。

方法

利用缺氧模拟仓（5 800 m）处理4 d后，构建小鼠缺氧肺损伤模型，肺组织切片HE染色评估肺损伤程度。利用缺氧工作站（1%O

浓度）处理小鼠肺泡上皮细胞系（murine lung epithelial-12，MLE12）24 h，构建MLE12缺氧细胞模型，Western blot分析检测TAZ表达。CCK-8实验评价肺泡上皮细胞（alveolar epithelial cells， AECs）增殖。免疫共沉淀（co-immunoprecipitation

Co-IP）实验验证TAZ与H2A.Z二者之间的相互作用。靶向剪切及转座酶标记技术（cleavage under targets and tagmentation，CUT

Tag）测序分析TAZ影响H2A.Z在染色质沉积情况。

结果

缺氧显著诱导小鼠肺组织肺泡萎缩及炎症浸润（

0.01）。缺氧培养显著上调MLE12细胞中TAZ蛋白表达（

0.05）。CCK-8实验发现，敲低TAZ后AECs增殖能力显著下降（

0.01）。Co-IP证实TAZ与H2A.Z存在物理相互作用。靶向剪切及转座酶标记技术（cleavage under targets and tagmentation，CUT

Tag）测序显示缺氧促进H2A.Z

在染色质上的沉积（常氧结合位点31 817，缺氧结合位点44 078），而TAZ敲低部分逆转此现象（结合位点37 840）。

结论

缺氧显著上调TAZ表达，后者与H2A.Z的结合并促进H2A.Z在染色质上的沉积，增强AECs增殖以应对缺氧损伤。

Abstract

Objective‍　‍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. Methods‍　‍A mouse model of hypoxic lung injury was established by being placed in a hypoxia chamber (simulating an altitude of 5 800 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%O

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. Results‍　‍Hypoxia significantly induced alveolar atrophy and inflammatory infiltration in mouse lung tissues(

0.01). Hypoxia significantly up-regulated the protein level of TAZ in MLE12 cells (

0.05). CCK-8 assay showed that knockdown of TAZ significantly reduced the proliferative capacity of AECs (

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 (31 817 peaks under normoxia

44 078 peaks under hypoxia)

which was partially reversed by TAZ knockdown (37 840 peaks). Conclusion‍　‍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.

关键词

Keywords

references

WANG R J ， MA S H ， YANG J ， et al . Sodium hydrosulfide protects rats from hypobaric-hypoxia-induced acute lung injury ［J］. Int J Mol Sci ， 2024 ， 25 （ 19 ）： 10734 . DOI： 10.3390/ijms251910734 http://dx.doi.org/10.3390/ijms251910734 .

BOREK I ， BIRNHUBER A ， VOELKEL N F ， et al . The vascular perspective on acute and chronic lung disease ［J］. J Clin Invest ， 2023 ， 133 （ 16 ）： e170502 . DOI： 10.1172/JCI170502 http://dx.doi.org/10.1172/JCI170502 .

KAMINSKI T W ， BRZOSKA T ， LI X Y ， et al . Lung microvascular occlusion by platelet-rich neutrophil-platelet aggregates promotes cigarette smoke-induced severe flu ［J］. JCI Insight ， 2024 ， 9 （ 2 ）： e167299 . DOI： 10.1172/jci.insight.167299 http://dx.doi.org/10.1172/jci.insight.167299 .

LIN X ， WANG H Y ， PU X Y . Protective mechanism of fdft1 in steroid hormone synthesis pathway in SD rats with acute hypoxic injury ［J］. Genes Genomics ， 2020 ， 42 （ 11 ）： 1319 - 1326 . DOI： 10.1007/s13258-020-00999-5 http://dx.doi.org/10.1007/s13258-020-00999-5 .

ZHAO Z ， HOU B ， TANG L ， et al . High-altitude hypoxia-induced rat alveolar cell injury by increasing autophagy ［J］. Int J Exp Pathol ， 2022 ， 103 （ 4 ）： 132 - 139 . DOI： 10.1111/iep.12434 http://dx.doi.org/10.1111/iep.12434 .

KOTTON D N ， MORRISEY E E . Lung regeneration： mechanisms， applications and emerging stem cell populations ［J］. Nat Med ， 2014 ， 20 （ 8 ）： 822 - 832 . DOI： 10.1038/nm.3642 http://dx.doi.org/10.1038/nm.3642 .

VAUGHAN A E ， BRUMWELL A N ， XI Y ， et al . Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury ［J］. Nature ， 2015 ， 517 （ 7536 ）： 621 - 625 . DOI： 10.1038/nature14112 http://dx.doi.org/10.1038/nature14112 .

RACKLEY C R ， STRIPP B R . Building and maintaining the epithelium of the lung ［J］. J Clin Invest ， 2012 ， 122 （ 8 ）： 2724 - 2730 . DOI： 10.1172/JCI60519 http://dx.doi.org/10.1172/JCI60519 .

BARKAUSKAS C E ， CRONCE M J ， RACKLEY C R ， et al . Type 2 alveolar cells are stem cells in adult lung ［J］. J Clin Invest ， 2013 ， 123 （ 7 ）： 3025 - 3036 . DOI： 10.1172/JCI68782 http://dx.doi.org/10.1172/JCI68782 .

WANG J ， PENG X Y ， YUAN N ， et al . Interplay between pulmonary epithelial stem cells and innate immune cells contribute to the repair and regeneration of ALI/ARDS ［J］. Transl Res ， 2024 ， 272 ： 111 - 125 . DOI： 10.1016/j.trsl.2024.05.012 http://dx.doi.org/10.1016/j.trsl.2024.05.012 .

ALYSANDRATOS K D ， HERRIGES M J ， KOTTON D N . Epithelial stem and progenitor cells in lung repair and regeneration ［J］. Annu Rev Physiol ， 2021 ， 83 ： 529 - 550 . DOI： 10.1146/annurev-physiol-041520-092904 http://dx.doi.org/10.1146/annurev-physiol-041520-092904 .

ZHANG Y S ， TU B ， SONG K ， et al . Epigenetic hallmarks in pulmonary fibrosis： new advances and perspectives ［J］. Cell Signal ， 2023 ， 110 ： 110842 . DOI： 10.1016/j.cellsig.2023.110842 http://dx.doi.org/10.1016/j.cellsig.2023.110842 .

CASTILLO C ， GRIECO M ， D’AMONE S ， et al . Hypoxia effects on glioblastoma progression through YAP/TAZ pathway regulation ［J］. Cancer Lett ， 2024 ， 588 ： 216792 . DOI： 10.1016/j.canlet.2024.216792 http://dx.doi.org/10.1016/j.canlet.2024.216792 .

XIANG L S ， GILKES D M ， HU H X ， et al . Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype ［J］. Oncotarget ， 2014 ， 5 （ 24 ）： 12509 - 12527 . DOI： 10.18632/oncotarget.2997 http://dx.doi.org/10.18632/oncotarget.2997 .

DIGIOVANNI G T ， HAN W ， SHERRILL T P ， et al . Epithelial Yap/Taz are required for functional alveolar regeneration following acute lung injury ［J］. JCI Insight ， 2023 ， 8 （ 19 ）： e173374 . DOI： 10.1172/jci.insight.173374 http://dx.doi.org/10.1172/jci.insight.173374 .

LACANNA R ， LICCARDO D ， ZHANG P ， et al . Yap/Taz regulate alveolar regeneration and resolution of lung inflammation ［J］. J Clin Invest ， 2019 ， 129 （ 5 ）： 2107 - 2122 . DOI： 10.1172/JCI125014 http://dx.doi.org/10.1172/JCI125014 .

ZHANG H X ， LI S S ， ZHOU R X ， et al . SRCAP complex promotes lung cancer progression by reprograming the oncogenic transcription of Hippo-YAP/TAZ signaling pathway ［J］. Cancer Lett ， 2024 ， 585 ： 216667 . DOI： 10.1016/j.canlet.2024.216667 http://dx.doi.org/10.1016/j.canlet.2024.216667 .

LONG H Z ， ZHANG L W ， LV M J ， et al . H2A.Z facilitates licensing and activation of early replication origins ［J］. Nature ， 2020 ， 577 （ 7791 ）： 576 - 581 . DOI： 10.1038/s41586-019-1877-9 http://dx.doi.org/10.1038/s41586-019-1877-9 .

ZHANG Y ， KU W L ， LIU S ， et al . Genome-wide identification of histone H2A and histone variant H2A.Z-interacting proteins by bPPI-seq ［J］. Cell Res ， 2017 ， 27 （ 10 ）： 1258 - 1274 . DOI： 10.1038/cr.2017.112 http://dx.doi.org/10.1038/cr.2017.112 .

ASPAL M ， ZEMANS R L . Mechanisms of ATII-to-ATI cell differentiation during lung regeneration ［J］. Int J Mol Sci ， 2020 ， 21 （ 9 ）： 3188 . DOI： 10.3390/ijms21093188 http://dx.doi.org/10.3390/ijms21093188 .

MIRCHANDANI A S ， JENKINS S J ， BAIN C C ， et al . Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation ［J］. Nat Immunol ， 2022 ， 23 （ 6 ）： 927 - 939 . DOI： 10.1038/s41590-022-01216-z http://dx.doi.org/10.1038/s41590-022-01216-z .

孟祥琼，陈婷，谢宏晨，等 . 缺氧特异性诱导肺血管内皮细胞黏附分子3表达以促进单核细胞黏附［J］. 陆军军医大学学报， 2025 ， 47 （ 1 ）： 51 - 59 . DOI： 10.16016/j.2097-0927.202407096 http://dx.doi.org/10.16016/j.2097-0927.202407096 .

MENG X Q ， CHEN T ， XIE H C ， et al . Hypoxia specifically induces CADM3 expression in pulmonary endothelial cells and promotes monocyte adhesion ［J］. J Army Med Univ ， 2025 ， 47 （ 1 ）： 51 - 59 . DOI： 10.16016/j.2097-0927.202407096 http://dx.doi.org/10.16016/j.2097-0927.202407096 .

LIN C R ， BAHMED K ， KOSMIDER B . Impaired alveolar re-epithelialization in pulmonary emphysema ［J］. Cells ， 2022 ， 11 （ 13 ）： 2055 . DOI： 10.3390/cells11132055 http://dx.doi.org/10.3390/cells11132055 .

LIU K ， MENG X F ， LIU Z X ， et al . Tracing the origin of alveolar stem cells in lung repair and regeneration ［J］. Cell ， 2024 ， 187 （ 10 ）： 2428 - 2445.e20 . DOI： 10.1016/j.cell.2024.03.010 http://dx.doi.org/10.1016/j.cell.2024.03.010 .

ØVREBØ J I ， MA Y Q ， EDGAR B A . Cell growth and the cell cycle： new insights about persistent questions ［J］. Bioessays ， 2022 ， 44 （ 11 ）： e2200150 . DOI： 10.1002/bies.202200150 http://dx.doi.org/10.1002/bies.202200150 .

PUCCI B ， KASTEN M ， GIORDANO A . Cell cycle and apoptosis ［J］. Neoplasia ， 2000 ， 2 （ 4 ）： 291 - 299 . DOI： 10.1038/sj.neo.7900101 http://dx.doi.org/10.1038/sj.neo.7900101 .

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