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Epigenetic modifications in the development of bronchopulmonary dysplasia: a review

Pediatric Research (2024)Cite this article

Abstract

While perinatal medicine advancements have bolstered survival outcomes for premature infants, bronchopulmonary dysplasia (BPD) continues to threaten their long-term health. Gene–environment interactions, mediated by epigenetic modifications such as DNA methylation, histone modification, and non-coding RNA regulation, take center stage in BPD pathogenesis. Recent discoveries link methylation variations across biological pathways with BPD. Also, the potential reversibility of histone modifications fuels new treatment avenues. The review also highlights the promise of utilizing mesenchymal stem cells and their exosomes as BPD therapies, given their ability to modulate non-coding RNA, opening novel research and intervention possibilities.

Impact

  • The complexity and universality of epigenetic modifications in the occurrence and development of bronchopulmonary dysplasia were thoroughly discussed.

  • Both molecular and cellular mechanisms contribute to the diverse nature of epigenetic changes, suggesting the need for deeper biochemical techniques to explore these molecular alterations.

  • The utilization of innovative cell-specific drug delivery methods like exosomes and extracellular vesicles holds promise in achieving precise epigenetic regulation.

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Data availability

This review article does not contain any primary data collection, and therefore, no new data were generated or analyzed as part of this study. The article is based solely on a comprehensive literature review of existing publications, which are cited within the text.

References

  1. Bapat, R. et al. A multidisciplinary quality improvement effort to reduce bronchopulmonary dysplasia incidence. J. Perinatol. 40, 681–687 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  2. DeMauro, S. B. Neurodevelopmental outcomes of infants with bronchopulmonary dysplasia. Pediatr. Pulmonol. 56, 3509–3517 (2021).

    Article  PubMed  Google Scholar 

  3. Lal, C. V. & Ambalavanan, N. Genetic predisposition to bronchopulmonary dysplasia. Semin. Perinatol. 39, 584–591 (2015).

    Article  PubMed  Google Scholar 

  4. Parad, R. B. et al. Role of Genetic susceptibility in the development of bronchopulmonary dysplasia. J. Pediatr. https://doi.org/10.1016/j.jpeds.2018.07.099 (2018).

  5. Sharma, S., Yang, I. V. & Schwartz, D. A. Epigenetic regulation of immune function in asthma. J. Allergy Clin. Immunol. 150, 259–265 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang, W., Song, M., Qu, J. & Liu, G.-H. Epigenetic modifications in cardiovascular aging and diseases. Circ. Res. 123, 773–786 (2018).

    Article  CAS  PubMed  Google Scholar 

  7. Teng, P.-C. et al. RNA modifications and epigenetics in modulation of lung cancer and pulmonary diseases. Int. J. Mol. Sci. https://doi.org/10.3390/ijms221910592 (2021).

  8. Moore, L. D., Le, T. & Fan, G. DNA methylation and its basic function. Neuropsychopharmacology 38, 23–38 (2013).

    Article  CAS  PubMed  Google Scholar 

  9. Walsh, C. P., Chaillet, J. R. & Bestor, T. H. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nat. Genet. 20, 116–117 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Chen, Z. & Zhang, Y. Role of mammalian DNA methyltransferases in development. Annu. Rev. Biochem. 89, 135–158 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Mattei, A. L., Bailly, N. & Meissner, A. DNA methylation: a historical perspective. Trends Genet. 38, 676–707 (2022).

    Article  CAS  PubMed  Google Scholar 

  12. Law, P.-P. & Holland, M. L. DNA methylation at the crossroads of gene and environment interactions. Essays Biochem. 63, 717–726 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kohli, R. M. & Zhang, Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502, 472–479 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Thomas, D. Methods for investigating gene-environment interactions in candidate pathway and genome-wide association studies. Annu. Rev. Public Health 31, 21–36 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Singer, B. D. A practical guide to the measurement and analysis of DNA methylation. Am. J. Respir. Cell Mol. Biol. 61, 417–428 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Xiong, Z. et al. EWAS Open Platform: integrated data, knowledge and toolkit for epigenome-wide association study. Nucleic Acids Res. 50, D1004–D1009 (2022).

    Article  CAS  PubMed  Google Scholar 

  17. Hadchouel, A. et al. Identification of SPOCK2 as a susceptibility gene for bronchopulmonary dysplasia. Am. J. Respir. Crit. Care Med. 184, 1164–1170 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Hadchouel, A. et al. Overexpression of Spock2 in mice leads to altered lung alveolar development and worsens lesions induced by hyperoxia. Am. J. Physiol. Lung Cell. Mol. Physiol. 319, L71–L81 (2020).

    Article  CAS  PubMed  Google Scholar 

  19. Herman, J. G. et al. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc. Natl Acad. Sci. USA 93, 9821–9826 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Frommer, M. et al. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc. Natl Acad. Sci. USA 89, 1827–1831 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhu, Y. et al. Hyperoxia-induced methylation decreases RUNX3 in a newborn rat model of bronchopulmonary dysplasia. Respir. Res. 16, 75 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lister, R. et al. Highly integrated single-base resolution maps of the epigenome in Arabidopsis. Cell 133, 523–536 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Meissner, A. et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells. Nature 454, 766–770 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Weber, M. et al. Chromosome-wide and promoter-specific analyses identify sites of differential DNA methylation in normal and transformed human cells. Nat. Genet. 37, 853–862 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Reyna-López, G. E., Simpson, J. & Ruiz-Herrera, J. Differences in DNA methylation patterns are detectable during the dimorphic transition of fungi by amplification of restriction polymorphisms. Mol. Gen. Genet. 253, 703–710 (1997).

    Article  PubMed  Google Scholar 

  26. Wang, X. et al. Epigenome-wide association study of bronchopulmonary dysplasia in preterm infants: results from the discovery-BPD program. Clin. Epigenetics 14, 57 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Cuna, A. et al. Alterations in gene expression and DNA methylation during murine and human lung alveolar septation. Am. J. Respir. Cell Mol. Biol. 53, 60–73 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang, H. et al. A genome-wide association study (GWAS) for bronchopulmonary dysplasia. Pediatrics 132, 290–297 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Reynolds, P. R., Stogsdill, J. A., Stogsdill, M. P. & Heimann, N. B. Up-regulation of receptors for advanced glycation end-products by alveolar epithelium influences cytodifferentiation and causes severe lung hypoplasia. Am. J. Respir. Cell Mol. Biol. 45, 1195–1202 (2011).

    Article  CAS  PubMed  Google Scholar 

  30. Habuchi, H. et al. Mice deficient in heparan sulfate 6-O-sulfotransferase-1 exhibit defective heparan sulfate biosynthesis, abnormal placentation, and late embryonic lethality. J. Biol. Chem. 282, 15578–15588 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Cho, H.-Y. et al. Prospective epigenome and transcriptome analyses of cord and peripheral blood from preterm infants at risk of bronchopulmonary dysplasia. Sci. Rep. 13, 12262 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Knight, A. K. et al. Relationship between epigenetic maturity and respiratory morbidity in preterm infants. J. Pediatr. https://doi.org/10.1016/j.jpeds.2018.02.074 (2018).

  33. Everson, T. M. et al. Serious neonatal morbidities are associated with differences in DNA methylation among very preterm infants. Clin. Epigenetics 12, 151 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chen, C.-M., Liu, Y.-C., Chen, Y.-J. & Chou, H.-C. Genome-wide analysis of DNA methylation in hyperoxia-exposed newborn rat lung. Lung 195, 661–669 (2017).

    Article  CAS  PubMed  Google Scholar 

  35. Wheaton, A. K., Agarwal, M., Jia, S. & Kim, K. K. Lung epithelial cell focal adhesion kinase signaling inhibits lung injury and fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 312, L722–L730 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Plosa, E. J. et al. Epithelial β1 integrin is required for lung branching morphogenesis and alveolarization. Development 141, 4751–4762 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Revhaug, C. et al. Immune system regulation affected by a murine experimental model of bronchopulmonary dysplasia: genomic and epigenetic findings. Neonatology 116, 269–277 (2019).

    Article  CAS  PubMed  Google Scholar 

  38. Sun, Y. et al. BMP7 regulates lung fibroblast proliferation in newborn rats with bronchopulmonary dysplasia. Mol. Med. Rep. 17, 6277–6284 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Millán-Zambrano, G., Burton, A., Bannister, A. J. & Schneider, R. Histone post-translational modifications - cause and consequence of genome function. Nat. Rev. Genet. 23, 563–580 (2022).

    Article  PubMed  Google Scholar 

  41. Zhang, Y. et al. Overview of histone modification. Adv. Exp. Med. Biol. https://doi.org/10.1007/978-981-15-8104-5_1 (2021).

  42. Boros, I. M. Histone modification in Drosophila. Brief. Funct. Genomics 11, 319–331 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Lawrence, M., Daujat, S. & Schneider, R. Lateral thinking: how histone modifications regulate gene expression. Trends Genet. 32, 42–56 (2016).

    Article  CAS  PubMed  Google Scholar 

  44. Bannister, A. J. & Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res. 21, 381–395 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lin, Y. et al. Role of histone post-translational modifications in inflammatory diseases. Front. Immunol. 13, 852272 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Yang, X. J. & Seto, E. HATs and HDACs: from structure, function and regulation to novel strategies for therapy and prevention. Oncogene 26, 5310–5318 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Fuchs, J., Demidov, D., Houben, A. & Schubert, I. Chromosomal histone modification patterns–from conservation to diversity. Trends Plant Sci. 11, 199–208 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Zhang, X. et al. Whole-genome analysis of histone H3 lysine 27 trimethylation in Arabidopsis. PLoS Biol. 5, e129 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Shvedunova, M. & Akhtar, A. Modulation of cellular processes by histone and non-histone protein acetylation. Nat. Rev. Mol. Cell Biol. 23, 329–349 (2022).

    Article  CAS  PubMed  Google Scholar 

  50. Mutskov, V. et al. Persistent interactions of core histone tails with nucleosomal DNA following acetylation and transcription factor binding. Mol. Cell. Biol. 18, 6293–6304 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Utley, R. T. et al. Transcriptional activators direct histone acetyltransferase complexes to nucleosomes. Nature 394, 498–502 (1998).

    Article  CAS  PubMed  Google Scholar 

  52. Seto, E. & Yoshida, M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 6, a018713 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Haque, M. E. et al. The GCN5: its biological functions and therapeutic potentials. Clin. Sci. 135, 231–257 (2021).

    Article  Google Scholar 

  54. Burckhardt, R. M. & Escalante-Semerena, J. C. Small-molecule acetylation by GCN5-related N-acetyltransferases in bacteria. Microbiol. Mol. Biol. Rev. https://doi.org/10.1128/MMBR.00090-19 (2020).

  55. Das, C., Lucia, M. S., Hansen, K. C. & Tyler, J. K. CBP/p300-mediated acetylation of histone H3 on lysine 56. Nature 459, 113–117 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tang, Y. et al. Fungal Rtt109 histone acetyltransferase is an unexpected structural homolog of metazoan p300/CBP. Nat. Struct. Mol. Biol. 15, 738–745 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Reichert, N., Choukrallah, M.-A. & Matthias, P. Multiple roles of class I HDACs in proliferation, differentiation, and development. Cell Mol. Life Sci. 69, 2173–2187 (2012).

    Article  CAS  PubMed  Google Scholar 

  58. Verdin, E., Dequiedt, F. & Kasler, H. G. Class II histone deacetylases: versatile regulators. Trends Genet. 19, 286–293 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. Vaquero, A., Sternglanz, R. & Reinberg, D. NAD+-dependent deacetylation of H4 lysine 16 by class III HDACs. Oncogene 26, 5505–5520 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Yang, X.-J. & Seto, E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat. Rev. Mol. Cell Biol. 9, 206–218 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yoshida, M. [Potent and specific inhibition of mammalian histone deacetylase both in vivo and in vitro by trichostatin A]. Tanpakushitsu Kakusan Koso 52, 1788–1789 (2007).

    PubMed  Google Scholar 

  62. Dokmanovic, M., Clarke, C. & Marks, P. A. Histone deacetylase inhibitors: overview and perspectives. Mol. Cancer Res. 5, 981–989 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Zhou, J., Wu, R. & Luo, H.-B. Inhibition mechanism of SAHA in HDAC: a revisit. Phys. Chem. Chem. Phys. 17, 29483–29488 (2015).

    Article  CAS  PubMed  Google Scholar 

  64. Coarfa, C. et al. Epigenetic response to hyperoxia in the neonatal lung is sexually dimorphic. Redox Biol. 37, 101718 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Londhe, V. A. et al. Hyperoxia impairs alveolar formation and induces senescence through decreased histone deacetylase activity and up-regulation of p21 in neonatal mouse lung. Pediatr. Res. 69, 371–377 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Buhimschi, C. S. et al. Antenatal N-acetylcysteine to improve outcomes of premature infants with intra-amniotic infection and inflammation (Triple I): randomized clinical trial. Pediatr. Res. 89, 175–184 (2021).

    Article  CAS  PubMed  Google Scholar 

  67. Ni, W. et al. Lipopolysaccharide induces up-regulation of TGF-α through HDAC2 in a rat model of bronchopulmonary dysplasia. PLoS ONE 9, e91083 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Noh, H. et al. Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury. Am. J. Physiol. Ren. Physiol. 297, F729–F739 (2009).

    Article  CAS  Google Scholar 

  69. Fang, W.-F. et al. Histone deacetylase 2 (HDAC2) attenuates lipopolysaccharide (LPS)-induced inflammation by regulating PAI-1 expression. J. Inflamm. 15, 3 (2018).

    Article  Google Scholar 

  70. Salimi, U. et al. Postnatal sepsis and bronchopulmonary dysplasia in premature infants: mechanistic insights into “new BPD”. Am. J. Respir. Cell Mol. Biol. 66, 137–145 (2022).

    Article  CAS  PubMed  Google Scholar 

  71. Menden, H. et al. Histone deacetylase 6 regulates endothelial MyD88-dependent canonical TLR signaling, lung inflammation, and alveolar remodeling in the developing lung. Am. J. Physiol. Lung Cell. Mol. Physiol. 317, L332–L346 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Wang, X. et al. Expression of histone deacetylase 3 instructs alveolar type I cell differentiation by regulating a Wnt signaling niche in the lung. Dev. Biol. 414, 161–169 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Wang, Y. et al. HDAC3-dependent epigenetic pathway controls lung alveolar epithelial cell remodeling and spreading via miR-17-92 and TGF-β signaling regulation. Dev. Cell. 36, 303–315 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang, D. et al. Involvement of Hdac3-mediated inhibition of microRNA cluster 17-92 in bronchopulmonary dysplasia development. Mol. Med. 26, 99 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Flodby, P. et al. Cell-specific expression of aquaporin-5 (Aqp5) in alveolar epithelium is directed by GATA6/Sp1 via histone acetylation. Sci. Rep. 7, 3473 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Horie, M. et al. Integrated single-cell RNA-sequencing analysis of aquaporin 5-expressing mouse lung epithelial cells identifies GPRC5A as a novel validated type i cell surface marker. Cells 9, 2460 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Chao, C.-M. et al. Neonatal exposure to hyperoxia leads to persistent disturbances in pulmonary histone signatures associated with NOS3 and STAT3 in a mouse model. Clin. Epigenetics 10, 37 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  78. Postberg, J. et al. CpG signalling, H2A.Z/H3 acetylation and microRNA-mediated deferred self-attenuation orchestrate foetal NOS3 expression. Clin. Epigenetics 7, 9 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  79. Zhu, L. et al. Hyperoxia arrests alveolar development through suppression of histone deacetylases in neonatal rats. Pediatr. Pulmonol. 47, 264–274 (2012).

    Article  PubMed  Google Scholar 

  80. Hyun, K., Jeon, J., Park, K. & Kim, J. Writing, erasing and reading histone lysine methylations. Exp. Mol. Med. 49, e324 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Fulton, M. D., Brown, T. & Zheng, Y. G. Mechanisms and inhibitors of histone arginine methylation. Chem. Rec. 18, 1792–1807 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Tsukada, Y.-i. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Stavropoulos, P., Blobel, G. & Hoelz, A. Crystal structure and mechanism of human lysine-specific demethylase-1. Nat. Struct. Mol. Biol. 13, 626–632 (2006).

    Article  CAS  PubMed  Google Scholar 

  84. Yang, M. et al. Structural basis of histone demethylation by LSD1 revealed by suicide inactivation. Nat. Struct. Mol. Biol. 14, 535–539 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Whetstine, J. R. et al. Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125, 467–481 (2006).

    Article  CAS  PubMed  Google Scholar 

  86. Lehnertz, B. et al. Suv39h-mediated histone H3 lysine 9 methylation directs DNA methylation to major satellite repeats at pericentric heterochromatin. Curr. Biol. 13, 1192–1200 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Li, P.-C. et al. Replication fork stability is essential for the maintenance of centromere integrity in the absence of heterochromatin. Cell Rep. 3, 638–645 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Rao, R. C. & Dou, Y. Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat. Rev. Cancer 15, 334–346 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Ren, K., Mou, Y.-N., Ying, S.-H. & Feng, M.-G. Conserved and noncanonical activities of two histone H3K36 methyltransferases required for insect-pathogenic lifestyle of Beauveria bassiana. J. Fungi https://doi.org/10.3390/jof7110956 (2021).

  90. Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Garcia-Bassets, I. et al. Histone methylation-dependent mechanisms impose ligand dependency for gene activation by nuclear receptors. Cell 128, 505–518 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Black, J. C., Van Rechem, C. & Whetstine, J. R. Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol. Cell 48, 491–507 (2012).

    Article  CAS  PubMed  Google Scholar 

  93. He, J., Nguyen, A. T. & Zhang, Y. KDM2b/JHDM1b, an H3K36me2-specific demethylase, is required for initiation and maintenance of acute myeloid leukemia. Blood 117, 3869–3880 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kim, J.-Y. et al. KDM3B is the H3K9 demethylase involved in transcriptional activation of lmo2 in leukemia. Mol. Cell Biol. 32, 2917–2933 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Berry, W. L. & Janknecht, R. KDM4/JMJD2 histone demethylases: epigenetic regulators in cancer cells. Cancer Res. 73, 2936–2942 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Klose, R. J. et al. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell 128, 889–900 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Tran, N., Broun A., Ge K. Lysine demethylase KDM6A in differentiation, development, and cancer. Mol. Cell. Biol. https://doi.org/10.1128/MCB.00341-20 (2020).

  98. Guccione, E. & Richard, S. The regulation, functions and clinical relevance of arginine methylation. Nat. Rev. Mol. Cell Biol. 20, 642–657 (2019).

    Article  CAS  PubMed  Google Scholar 

  99. Fedoriw, A. et al. Anti-tumor activity of the type I PRMT inhibitor, GSK3368715, synergizes with PRMT5 inhibition through MTAP loss. Cancer Cell https://doi.org/10.1016/j.ccell.2019.05.014 (2019).

  100. Wu, Q., Schapira, M., Arrowsmith, C. H. & Barsyte-Lovejoy, D. Protein arginine methylation: from enigmatic functions to therapeutic targeting. Nat. Rev. Drug Discov. 20, 509–530 (2021).

    Article  CAS  PubMed  Google Scholar 

  101. Chervona, Y. & Costa, M. The control of histone methylation and gene expression by oxidative stress, hypoxia, and metals. Free Radic. Biol. Med. 53, 1041–1047 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sugar, S. S. et al. Perinatal inflammation alters histone 3 and histone 4 methylation patterns: effects of MiR-29b supplementation. Redox Biol. 38, 101783 (2021).

    Article  CAS  PubMed  Google Scholar 

  103. Ferreira, T. R. et al. PRMT7 regulates RNA-binding capacity and protein stability in Leishmania parasites. Nucleic Acids Res. 48, 5511–5526 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wu, Y. et al. Analysis of two birth tissues provides new insights into the epigenetic landscape of neonates born preterm. Clin. Epigenetics 11, 26 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Chen, Y.-D. et al. Functional roles of C/EBPα and SUMO‑modification in lung development. Int. J. Mol. Med. 40, 1037–1046 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Dong, W. et al. Role of the SENP1-SIRT1 pathway in hyperoxia-induced alveolar epithelial cell injury. Free Radic. Biol. Med. 173, 142–150 (2021).

    Article  CAS  PubMed  Google Scholar 

  107. Tan, F. et al. Attenuated SUMOylation of sirtuin 1 in premature neonates with bronchopulmonary dysplasia. Mol. Med. Rep. 17, 1283–1288 (2018).

    CAS  PubMed  Google Scholar 

  108. Zhu, Y. et al. Sumoylation of CCAAT-enhancer-binding protein α inhibits lung differentiation in bronchopulmonary dysplasia model rats. J. Cell. Mol. Med. 24, 7067–7071 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhu, Y. et al. [Dynamic expression and role of SUMO-modified C/EBPα in preterm rats with bronchopulmonary dysplasisa induced by hyperoxia exposure]. Zhongguo Dang Dai Er Ke Za Zhi 20, 403–409 (2018).

    PubMed  Google Scholar 

  110. Hombach, S. & Kretz, M. Non-coding RNAs: classification, biology and functioning. Adv. Exp. Med. Biol. https://doi.org/10.1007/978-3-319-42059-2_1 (2016).

  111. Morselli, M. & Dieci, G. Epigenetic regulation of human non-coding RNA gene transcription. Biochem. Soc. Trans. 50, 723–736 (2022).

    Article  CAS  PubMed  Google Scholar 

  112. Martianov, I. et al. Repression of the human dihydrofolate reductase gene by a non-coding interfering transcript. Nature 445, 666–670 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Qin, W. X. et al. EZH2-mediated H3K27me3 enrichment on the lncRNA MEG3 promoter regulates the growth and metastasis of glioma cells by regulating miR-21-3p. Eur. Rev. Med. Pharm. Sci. 24, 3204–3214 (2020).

    Google Scholar 

  114. Jiang, B. et al. lncRNA PVT1 promotes hepatitis B virus‑positive liver cancer progression by disturbing histone methylation on the c‑Myc promoter. Oncol. Rep. 43, 718–726 (2020).

    CAS  PubMed  Google Scholar 

  115. Huntzinger, E. & Izaurralde, E. Gene silencing by microRNAs: contributions of translational repression and mRNA decay. Nat. Rev. Genet. https://doi.org/10.1038/nrg2936 (2011).

  116. Li, J. & Zhang, Z. miRNA regulatory variation in human evolution. Trends Genet. 29, 116–124 (2013).

    Article  PubMed  Google Scholar 

  117. Ender, C. et al. A human snoRNA with microRNA-like functions. Mol. Cell 32, 519–528 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Brameier, M. et al. Human box C/D snoRNAs with miRNA like functions: expanding the range of regulatory RNAs. Nucleic Acids Res. 39, 675–686 (2011).

    Article  CAS  PubMed  Google Scholar 

  119. Lambert, M., Benmoussa, A. & Provost, P. Small non-coding RNAs derived from eukaryotic ribosomal RNA. Noncoding RNA https://doi.org/10.3390/ncrna5010016 (2019).

  120. Siomi, M. C., Sato, K., Pezic, D. & Aravin, A. A. PIWI-interacting small RNAs: the vanguard of genome defence. Nat. Rev. Mol. Cell Biol. 12, 246–258 (2011).

    Article  CAS  PubMed  Google Scholar 

  121. Luteijn, M. J. & Ketting, R. F. PIWI-interacting RNAs: from generation to transgenerational epigenetics. Nat. Rev. Genet. 14, 523–534 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. Kristensen, L. S. et al. The biogenesis, biology and characterization of circular RNAs. Nat. Rev. Genet. 20, 675–691 (2019).

    Article  CAS  PubMed  Google Scholar 

  123. Zhang, G. et al. Comprehensive analysis of long noncoding RNA (lncRNA)-chromatin interactions reveals lncRNA functions dependent on binding diverse regulatory elements. J. Biol. Chem. 294, 15613–15622 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhang, M. et al. Long non-coding RNA MALAT1 plays a protective role in bronchopulmonary dysplasia via the inhibition of apoptosis and interaction with the Keap1/Nrf2 signal pathway. Transl. Pediatr. 10, 265–275 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Cai, C. et al. Long non-coding RNA MALAT1 protects preterm infants with bronchopulmonary dysplasia by inhibiting cell apoptosis. BMC Pulm. Med. 17, 199 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  126. Chen, J.-H. et al. Long non-coding RNA MALAT1 targeting STING transcription promotes bronchopulmonary dysplasia through regulation of CREB. J. Cell. Mol. Med. 24, 10478–10492 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Zhang, Y. et al. Pulmonary endothelial cells exhibit sexual dimorphism in their response to hyperoxia. Am. J. Physiol. Heart Circ. Physiol. 315, H1287–H1292 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Zhang, L., Bai, X. & Yan, W. LncRNA-MALAT1, as a biomarker of neonatal BPD, exacerbates the pathogenesis of BPD by targeting miR-206. Am. J. Transl. Res. 13, 462–479 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Zhong, Q. et al. Long non-coding RNA TUG1 modulates expression of elastin to relieve bronchopulmonary dysplasia via sponging miR-29a-3p. Front. Pediatr. 8, 573099 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  130. Yuan, W. et al. Silencing of long non-coding RNA X inactive specific transcript (Xist) contributes to suppression of bronchopulmonary dysplasia induced by hyperoxia in newborn mice via microRNA-101-3p and the transforming growth factor-beta 1 (TGF-β1)/Smad3 axis. Med. Sci. Monit. 26, e922424 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Bao, T. et al. Expression of long noncoding RNA uc.375 in bronchopulmonary dysplasia and its function in the proliferation and apoptosis of mouse alveolar epithelial cell line MLE 12. Front. Physiol. 13, 971732 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Yao, Q., Chen, Y. & Zhou, X. The roles of microRNAs in epigenetic regulation. Curr. Opin. Chem. Biol. 51, 11–17 (2019).

    Article  CAS  PubMed  Google Scholar 

  133. Freeman, A. et al. MicroRNA 219-5p inhibits alveolarization by reducing platelet derived growth factor receptor-alpha. Respir. Res. 22, 57 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Shen, Y.-Q. et al. MicroRNA‑431 inhibits the expression of surfactant proteins through the BMP4/activin/TGF‑β signaling pathway by targeting SMAD4. Int. J. Mol. Med. 45, 1571–1582 (2020).

    CAS  PubMed  Google Scholar 

  135. Li, S. et al. The role of miR-431-5p in regulating pulmonary surfactant expression in vitro. Cell. Mol. Biol. Lett. 24, 25 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Olave, N. et al. Regulation of alveolar septation by microRNA-489. Am. J. Physiol. Lung Cell. Mol. Physiol. 310, L476–L487 (2016).

    Article  PubMed  Google Scholar 

  137. Panni, S., Lovering, R. C., Porras, P. & Orchard, S. Non-coding RNA regulatory networks. Biochim. Biophys. Acta Gene Regul. Mech. 1863, 194417 (2020).

    Article  CAS  PubMed  Google Scholar 

  138. Lun, Y., Hu, J. & Zuming, Y. Circular RNAs expression profiles and bioinformatics analysis in bronchopulmonary dysplasia. J. Clin. Lab. Anal. 37, e24805 (2023).

    Article  CAS  PubMed  Google Scholar 

  139. Cheng, H. et al. Insights into the expression profiles and functions of circRNAs in a newborn hyperoxia-induced rat bronchopulmonary dysplasia model. J. Gene Med. 22, e3163 (2020).

    Article  CAS  PubMed  Google Scholar 

  140. Mao, X. et al. Next-generation sequencing to investigate circular RNA profiles in the peripheral blood of preterm neonates with bronchopulmonary dysplasia. J. Clin. Lab. Anal. 34, e23260 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Wang, J. et al. Changing expression profiles of mRNA, lncRNA, circRNA, and miRNA in lung tissue reveal the pathophysiological of bronchopulmonary dysplasia (BPD) in mouse model. J. Cell. Biochem. 120, 9369–9380 (2019).

    Article  CAS  PubMed  Google Scholar 

  142. Anastasiadou, E., Jacob, L. S. & Slack, F. J. Non-coding RNA networks in cancer. Nat. Rev. Cancer. https://doi.org/10.1038/nrc.2017.99 (2018).

  143. Mattick, J. S. & Makunin, I. V. Non-coding RNA. Hum. Mol. Genet. 15, R17–R29 (2006).

    Article  CAS  PubMed  Google Scholar 

  144. Chen, Y.-F. et al. Promotion of bronchopulmonary dysplasia progression using circular RNA circabcc4 via facilitating PLA2G6 expression by sequestering miR-663a. Front. Cell Dev. Biol. 8, 585541 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Genschmer, K. R., et al. Activated PMN exosomes: pathogenic entities causing matrix destruction and disease in the lung. Cell https://doi.org/10.1016/j.cell.2018.12.002 (2019).

  146. Wang, Y. et al. CircRNA, lncRNA, and mRNA profiles of umbilical cord blood exosomes from preterm newborns showing bronchopulmonary dysplasia. Eur. J. Pediatr. 181, 3345–3365 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Zhong, X.-Q. et al. Umbilical cord blood-derived exosomes from very preterm infants with bronchopulmonary dysplasia impaired endothelial angiogenesis: roles of exosomal microRNAs. Front. Cell Dev. Biol. 9, 637248 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Willis, G. R. et al. Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation. Am. J. Respir. Crit. Care Med. 197, 104–116 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Braun, R. K. et al. Intraperitoneal injection of MSC-derived exosomes prevent experimental bronchopulmonary dysplasia. Biochem. Biophys. Res. Commun. 503, 2653–2658 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Wu, Y. et al. Mechanism of adipose-derived mesenchymal stem cell-derived extracellular vesicles carrying miR-21-5p in hyperoxia-induced lung injury. Stem Cell Rev. Rep. 18, 1007–1024 (2022).

    Article  CAS  PubMed  Google Scholar 

  151. Willis, G. R. et al. Mesenchymal stromal cell-derived small extracellular vesicles restore lung architecture and improve exercise capacity in a model of neonatal hyperoxia-induced lung injury. J. Extracell. Vesicles 9, 1790874 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Yang, W. et al. Bone mesenchymal stem cell-derived exosomes prevent hyperoxia-induced apoptosis of primary type II alveolar epithelial cells in vitro. PeerJ 10, e13692 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Willis, G. R. et al. Extracellular vesicles protect the neonatal lung from hyperoxic injury through the epigenetic and transcriptomic reprogramming of myeloid cells. Am. J. Respir. Crit. Care Med. 204, 1418–1432 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We wish to thank Ana Hou for guidance and support during the completion of this review. Figures were created using biorender.com.

Funding

The study was supported by grants from the Social Development Major Projects of Liaoning Province (2020JH1/1030001), Key Research and Development Program Joint Program of Liaoning Province (2020JH2/10300132), Public Welfare Fund of China Foundation for International Medical Exchange (z-2019-41-2101-04), and the 345lent project of the China Medical University affiliated Shengjing Hospital.

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  1. Department of Pediatrics, Sheng Jing Hospital of China Medical University, Shenyang, China

    Lichuan Wang, Jun Xiao, Bohan Zhang & Ana Hou

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  1. Lichuan Wang
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Contributions

L.W., A.H., J.X., and B.Z. collaborated on the extensive literature search. L.W. took on the pivotal role of drafting the initial manuscript and spearheading the systematic literature review. A.H. contributed valuable insights by critically appraising the manuscript with a focus on intellectual content. J.X. and B.Z. provided essential support in the meticulous preparation of the manuscript.

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Correspondence to Ana Hou.

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Wang, L., Xiao, J., Zhang, B. et al. Epigenetic modifications in the development of bronchopulmonary dysplasia: a review. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03167-7

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