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Bivalent Regulation and Related Mechanisms of H3K4/27/9me3 in Stem Cells

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Abstract

The "bivalent domain" is a unique histone modification region consisting of two histone tri-methylation modifications. Over the years, it has been revealed that the maintenance and dynamic changes of the bivalent domains play a vital regulatory role in the differentiation of various stem cell systems, as well as in other cells, such as immunomodulation. Tri-methylation modifications involved in the formation of the bivalent domains are interrelated and mutually regulated, thus regulating many life processes of cells. Tri-methylation of histone H3 at lysine 4 (H3K4me3), tri-methylation of histone H3 at lysine 9 (H3K9me3) and tri-methylation of histone H3 at lysine 27 (H3K27me3) are the main tri-methylation modifications involved in the formation of bivalent domains. The three form different bivalent domains in pairs. Furthermore, it is equally clear that H3K4me3 is a positive regulator of transcription and that H3K9me3/H3K27me3 are negative regulators. Enzymes related to the regulation of histone methylation play a significant role in the "homeostasis" and "breaking homeostasis" of the bivalent domains. Bivalent domains regulate target genes, upstream transcription, downstream targeting regulation and related cytokines during the establishment and breakdown of homeostasis, and exert the specific regulation of stem cells. Indeed, a unified mechanism to explain the bivalent modification in all stem cells has been difficult to define, and whether the bivalent modification is antagonistic in inducing the differentiation of homologous stem cells is controversial. In this review, we focus on the different bivalent modifications in several key stem cells and explore the main mechanisms and effects of these modifications involved. Finally, we discussed the close relationship between bivalent domains and immune cells, and put forward the prospect of the application of bivalent domains in the field of stem cells.

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The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Yang, X., Tian, D. C., He, W., et al. (2020). Cellular and molecular imaging for stem cell tracking in neurological diseases. Stroke Vasc Neurol. https://doi.org/10.1136/svn-2020-000408

    Article  PubMed  PubMed Central  Google Scholar 

  2. Zamani, A. R. N., Saberianpour, S., Geranmayeh, M. H., et al. (2020). Modulatory effect of photobiomodulation on stem cell epigenetic memory: A highlight on differentiation capacity. Lasers in Medical Science, 35(2), 299–306. https://doi.org/10.1007/s10103-019-02873-7

    Article  PubMed  Google Scholar 

  3. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676. https://doi.org/10.1016/j.cell.2006.07.024

    Article  CAS  Google Scholar 

  4. Wu, Y., & Zhang, W. (2021). The role of E3s in regulating pluripotency of embryonic stem cells and induced pluripotent stem cells. Int J Mol Sci, 22(3), 1168. https://doi.org/10.3390/ijms22031168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zhang, X. H., & Jin, Z. B. (2021). Patient iPSC-derived retinal organoids: Observable retinal diseases in-a-dish. Histology and Histopathology, 18307. https://doi.org/10.14670/hh-18-307

  6. Introna, M., & Golay, J. (2020). tolerance to bone marrow transplantation: Do mesenchymal stromal cells still have a future for acute or chronic GvHD? Frontiers in Immunology, 11, 609063. https://doi.org/10.3389/fimmu.2020.609063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Danišovič, L., Varga, I., & Polák, S. (2012). Growth factors and chondrogenic differentiation of mesenchymal stem cells. Tissue and Cell, 44(2), 69–73. https://doi.org/10.1016/j.tice.2011.11.005

    Article  CAS  PubMed  Google Scholar 

  8. Murphy, M. B., Moncivais, K., & Caplan, A. I. (2013). Mesenchymal stem cells: Environmentally responsive therapeutics for regenerative medicine. Experimental & Molecular Medicine, 45(11), e54. https://doi.org/10.1038/emm.2013.94

    Article  CAS  Google Scholar 

  9. Fukuda, K., & Shinkai, Y. (2020). SETDB1-mediated silencing of retroelements. Viruses, 12(6), 596. https://doi.org/10.3390/v12060596

    Article  CAS  PubMed Central  Google Scholar 

  10. Kidder, B. L., Hu, G., & Zhao, K. (2014). KDM5B focuses H3K4 methylation near promoters and enhancers during embryonic stem cell self-renewal and differentiation. Genome biology, 15(2), R32. https://doi.org/10.1186/gb-2014-15-2-r32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wright, H., Aylwin, C. F., Toro, C. A., et al. (2021). Polycomb represses a gene network controlling puberty via modulation of histone demethylase Kdm6b expression. Scientific Reports, 11(1), 1996. https://doi.org/10.1038/s41598-021-81689-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Matsumura, Y., Nakaki, R., Inagaki, T., et al. (2015). H3K4/H3K9me3 bivalent chromatin domains targeted by lineage-specific DNA methylation pauses adipocyte differentiation. Molecular Cell, 60(4), 584–596. https://doi.org/10.1016/j.molcel.2015.10.025

    Article  CAS  PubMed  Google Scholar 

  13. Wang, L., Jin, Q., Lee, J. E., et al. (2010). Histone H3K27 methyltransferase Ezh2 represses Wnt genes to facilitate adipogenesis. Proceedings of the National Academy of Sciences of the United States of America, 107(16), 7317–7322. https://doi.org/10.1073/pnas.1000031107

    Article  PubMed  PubMed Central  Google Scholar 

  14. Van Nuland, R., Smits, A. H., Pallaki, P., et al. (2013). Quantitative dissection and stoichiometry determination of the human SET1/MLL histone methyltransferase complexes. Molecular and Cellular Biology, 33(10), 2067–2077. https://doi.org/10.1128/mcb.01742-12

    Article  PubMed  PubMed Central  Google Scholar 

  15. Aoki, R., Chiba, T., Miyagi, S., et al. (2010). The polycomb group gene product Ezh2 regulates proliferation and differentiation of murine hepatic stem/progenitor cells. Journal of Hepatology, 52(6), 854–863. https://doi.org/10.1016/j.jhep.2010.01.027

    Article  CAS  PubMed  Google Scholar 

  16. Wei, H., Dong, X., You, Y., et al. (2021). OLIG2 regulates lncRNAs and its own expression during oligodendrocyte lineage formation. BMC Biology, 19(1), 132. https://doi.org/10.1186/s12915-021-01057-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Choi, H. J., Park, J. H., Park, M., et al. (2015). UTX inhibits EMT-induced breast CSC properties by epigenetic repression of EMT genes in cooperation with LSD1 and HDAC1. EMBO Rep, 16(10), 1288–1298. https://doi.org/10.15252/embr.201540244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Le Boiteux, E., Court, F., Guichet, P. O., et al. (2021). Widespread overexpression from the four DNA hypermethylated HOX clusters in aggressive (IDHwt) glioma is associated with H3K27me3 depletion and alternative promoter usage. Molecular Oncology. https://doi.org/10.1002/1878-0261.12944

    Article  PubMed  PubMed Central  Google Scholar 

  19. Ji, G., Zhou, W., Du, J., et al. (2021). PCGF1 promotes epigenetic activation of stemness markers and colorectal cancer stem cell enrichment. Cell Death & Disease, 12(7), 633. https://doi.org/10.1038/s41419-021-03914-2

    Article  CAS  Google Scholar 

  20. Bernstein, B. E., Mikkelsen, T. S., Xie, X., et al. (2006). A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell, 125(2), 315–326. https://doi.org/10.1016/j.cell.2006.02.041

    Article  CAS  PubMed  Google Scholar 

  21. Howe, F. S., Fischl, H., Murray, S. C., et al. (2017). Is H3K4me3 instructive for transcription activation? BioEssays, 39(1), 1–12. https://doi.org/10.1002/bies.201600095

    Article  CAS  PubMed  Google Scholar 

  22. Barski, A., Cuddapah, S., Cui, K., et al. (2007). High-resolution profiling of histone methylations in the human genome. Cell, 129(4), 823–837. https://doi.org/10.1016/j.cell.2007.05.009

    Article  CAS  PubMed  Google Scholar 

  23. Margueron, R., & Reinberg, D. (2011). The Polycomb complex PRC2 and its mark in life. Nature, 469(7330), 343–349. https://doi.org/10.1038/nature09784

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pauler, F. M., Sloane, M. A., Huang, R., et al. (2009). H3K27me3 forms BLOCs over silent genes and intergenic regions and specifies a histone banding pattern on a mouse autosomal chromosome. Genome research, 19(2), 221–233. https://doi.org/10.1101/gr.080861.108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhang, J., Matsumura, Y., Kano, Y., et al. (2021). Ubiquitination dependent and independent repression of target genes by SETDB1 reveals a context dependent role for its methyltransferase activity during adipogenesis. Genes to Cells. https://doi.org/10.1111/gtc.12868

    Article  PubMed  Google Scholar 

  26. Yoo, S., & Bieda, M. C. (2014). Differences among brain tumor stem cell types and fetal neural stem cells in focal regions of histone modifications and DNA methylation, broad regions of modifications, and bivalent promoters. BMC Genomics, 15(1), 724. https://doi.org/10.1186/1471-2164-15-724

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Günther, T., & Grundhoff, A. (2010). The epigenetic landscape of latent Kaposi sarcoma-associated herpesvirus genomes. PLoS Pathogens, 6(6), e1000935. https://doi.org/10.1371/journal.ppat.1000935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cao, Z., Li, Y., Chen, Z., et al. (2015). genome-wide dynamic profiling of histone methylation during nuclear transfer-mediated porcine somatic cell reprogramming. PLoS ONE, 10(12), e0144897. https://doi.org/10.1371/journal.pone.0144897

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Roth, S. Y., Denu, J. M., & Allis, C. D. (2001). Histone acetyltransferases. Annual Review of Biochemistry, 70, 81–120. https://doi.org/10.1146/annurev.biochem.70.1.81

    Article  CAS  PubMed  Google Scholar 

  30. Zhao, W., Qiao, L., Yan, S., et al. (2021). Mathematical modeling of histone modifications reveals the formation mechanism and function of bivalent chromatin. iScience, 24(7), 102732. https://doi.org/10.1016/j.isci.2021.102732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Igolkina, A. A., Zinkevich, A., Karandasheva, K. O., et al. (2019). H3K4me3, H3K9ac, H3K27ac, H3K27me3 and H3K9me3 histone tags suggest distinct regulatory evolution of open and condensed chromatin landmarks. Cells, 8(9), 1034. https://doi.org/10.3390/cells8091034

    Article  CAS  PubMed Central  Google Scholar 

  32. Zhang, T., Cooper, S., & Brockdorff, N. (2015). The interplay of histone modifications - writers that read. EMBO Rep, 16(11), 1467–1481. https://doi.org/10.15252/embr.201540945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Harikumar, A., & Meshorer, E. (2015). Chromatin remodeling and bivalent histone modifications in embryonic stem cells. EMBO Rep, 16(12), 1609–1619. https://doi.org/10.15252/embr.201541011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li, F., Wan, M., Zhang, B., et al. (2018). Bivalent histone modifications and development. Current Stem Cell Research & Therapy, 13(2), 83–90. https://doi.org/10.2174/1574888x12666170123144743

    Article  CAS  Google Scholar 

  35. Saksouk, N., Simboeck, E., & Déjardin, J. (2015). Constitutive heterochromatin formation and transcription in mammals. Epigenetics & Chromatin, 8, 3. https://doi.org/10.1186/1756-8935-8-3

    Article  CAS  Google Scholar 

  36. Voigt, P., Tee, W. W., & Reinberg, D. (2013). A double take on bivalent promoters. Genes & Development, 27(12), 1318–1338. https://doi.org/10.1101/gad.219626.113

    Article  CAS  Google Scholar 

  37. Piunti, A., & Shilatifard, A. (2016). Epigenetic balance of gene expression by Polycomb and COMPASS families. Science, 352(6290), aad9780. https://doi.org/10.1126/science.aad9780

    Article  CAS  PubMed  Google Scholar 

  38. Mohan, M., Herz, H. M., Smith, E. R., et al. (2011). The COMPASS family of H3K4 methylases in Drosophila. Molecular and Cellular Biology, 31(21), 4310–4318. https://doi.org/10.1128/mcb.06092-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bosgana, P., Nikou, S., Dimitrakopoulos, F. I., et al. (2020). H3K4 Methylation status and lysine specific methyltransferase KMT2C expression correlate with prognosis in lung adenocarcinoma. Current Molecular Pharmacology. https://doi.org/10.2174/1874467213999200831130739

    Article  Google Scholar 

  40. Chetverina, D. A., Lomaev, D. V., & Erokhin, M. M. (2020). Polycomb and trithorax group proteins: The long road from mutations in drosophila to use in medicine. Acta Naturae, 12(4), 66–85. https://doi.org/10.32607/actanaturae.11090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vastenhouw, N. L., & Schier, A. F. (2012). Bivalent histone modifications in early embryogenesis. Current Opinion in Cell Biology, 24(3), 374–386. https://doi.org/10.1016/j.ceb.2012.03.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Vinogradova, M., Gehling, V. S., Gustafson, A., et al. (2016). An inhibitor of KDM5 demethylases reduces survival of drug-tolerant cancer cells. Nature Chemical Biology, 12(7), 531–538. https://doi.org/10.1038/nchembio.2085

    Article  CAS  PubMed  Google Scholar 

  43. Yu, C., Xiong, C., Tang, J., et al. (2021). Histone demethylase JMJD3 protects against renal fibrosis by suppressing TGFβ and Notch signaling and preserving PTEN expression. Theranostics, 11(6), 2706–2721. https://doi.org/10.7150/thno.48679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Leng, X., Wang, J., An, N., et al. (2020). Histone 3 lysine-27 demethylase KDM6A coordinates with KMT2B to play an oncogenic role in NSCLC by regulating H3K4me3. Oncogene, 39(41), 6468–6479. https://doi.org/10.1038/s41388-020-01449-y

    Article  CAS  PubMed  Google Scholar 

  45. Rea, S., Eisenhaber, F., O’carroll, D., et al. (2000). Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature, 406(6796), 593–599. https://doi.org/10.1038/35020506

    Article  CAS  PubMed  Google Scholar 

  46. Schultz, D. C., Ayyanathan, K., Negorev, D., et al. (2002). SETDB1: A novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes & Development, 16(8), 919–932. https://doi.org/10.1101/gad.973302

    Article  CAS  Google Scholar 

  47. Dodge, J. E., Kang, Y. K., Beppu, H., et al. (2004). Histone H3–K9 methyltransferase ESET is essential for early development. Molecular and Cellular Biology, 24(6), 2478–2486. https://doi.org/10.1128/mcb.24.6.2478-2486.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liu, S., Brind’amour, J., Karimi, M. M., et al. (2014). Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells. Genes & Development, 28(18), 2041–2055. https://doi.org/10.1101/gad.244848.114

    Article  CAS  Google Scholar 

  49. Tan, S. L., Nishi, M., Ohtsuka, T., et al. (2012). Essential roles of the histone methyltransferase ESET in the epigenetic control of neural progenitor cells during development. Development, 139(20), 3806–3816. https://doi.org/10.1242/dev.082198

    Article  CAS  PubMed  Google Scholar 

  50. Koide, S., Oshima, M., Takubo, K., et al. (2016). Setdb1 maintains hematopoietic stem and progenitor cells by restricting the ectopic activation of nonhematopoietic genes. Blood, 128(5), 638–649. https://doi.org/10.1182/blood-2016-01-694810

    Article  CAS  PubMed  Google Scholar 

  51. Takikita, S., Muro, R., Takai, T., et al. (2016). A histone methyltransferase ESET is critical for T cell development. The Journal of Immunology, 197(6), 2269–2279. https://doi.org/10.4049/jimmunol.1502486

    Article  CAS  PubMed  Google Scholar 

  52. Collins, P. L., Kyle, K. E., Egawa, T., et al. (2015). The histone methyltransferase SETDB1 represses endogenous and exogenous retroviruses in B lymphocytes. Proc Natl Acad Sci U S A, 112(27), 8367–8372. https://doi.org/10.1073/pnas.1422187112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pasquarella, A., Ebert, A., Pereira De Almeida, G., et al. (2016). Retrotransposon derepression leads to activation of the unfolded protein response and apoptosis in pro-B cells. Development, 143(10), 1788–1799. https://doi.org/10.1242/dev.130203

    Article  CAS  PubMed  Google Scholar 

  54. Lawson, K. A., Teteak, C. J., Gao, J., et al. (2013). ESET histone methyltransferase regulates osteoblastic differentiation of mesenchymal stem cells during postnatal bone development. FEBS Letters, 587(24), 3961–3967. https://doi.org/10.1016/j.febslet.2013.10.028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sachs, M., Onodera, C., Blaschke, K., et al. (2013). Bivalent chromatin marks developmental regulatory genes in the mouse embryonic germline in vivo. Cell Reports, 3(6), 1777–1784. https://doi.org/10.1016/j.celrep.2013.04.032

    Article  CAS  PubMed  Google Scholar 

  56. Khromov, T., Pantakani, D. V., Nolte, J., et al. (2011). Global and gene-specific histone modification profiles of mouse multipotent adult germline stem cells. Molecular Human Reproduction, 17(3), 166–174. https://doi.org/10.1093/molehr/gaq085

    Article  CAS  PubMed  Google Scholar 

  57. Jeon, A. J., & Tucker-Kellogg, G. (2020). Bivalent genes that undergo transcriptional switching identify networks of key regulators of embryonic stem cell differentiation. BMC Genomics, 21(Suppl 10), 614. https://doi.org/10.1186/s12864-020-07009-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cui, P., Liu, W., Zhao, Y., et al. (2012). Comparative analyses of H3K4 and H3K27 trimethylations between the mouse cerebrum and testis. Genomics, Proteomics & Bioinformatics, 10(2), 82–93. https://doi.org/10.1016/j.gpb.2012.05.007

    Article  CAS  Google Scholar 

  59. Li, B., Howe, L., Anderson, S., et al. (2003). The Set2 histone methyltransferase functions through the phosphorylated carboxyl-terminal domain of RNA polymerase II. Journal of Biological Chemistry, 278(11), 8897–8903. https://doi.org/10.1074/jbc.M212134200

    Article  CAS  Google Scholar 

  60. Pray-Grant, M. G., Daniel, J. A., Schieltz, D., et al. (2005). Chd1 chromodomain links histone H3 methylation with SAGA- and SLIK-dependent acetylation. Nature, 433(7024), 434–438. https://doi.org/10.1038/nature03242

    Article  CAS  PubMed  Google Scholar 

  61. Santos-Rosa, H., Schneider, R., Bernstein, B. E., et al. (2003). Methylation of histone H3 K4 mediates association of the Isw1p ATPase with chromatin. Molecular Cell, 12(5), 1325–1332. https://doi.org/10.1016/s1097-2765(03)00438-6

    Article  CAS  PubMed  Google Scholar 

  62. Sims, R. J., 3rd., Chen, C. F., Santos-Rosa, H., et al. (2005). Human but not yeast CHD1 binds directly and selectively to histone H3 methylated at lysine 4 via its tandem chromodomains. Journal of Biological Chemistry, 280(51), 41789–41792. https://doi.org/10.1074/jbc.C500395200

    Article  CAS  Google Scholar 

  63. Wysocka, J., Swigut, T., Milne, T. A., et al. (2005). WDR5 associates with histone H3 methylated at K4 and is essential for H3 K4 methylation and vertebrate development. Cell, 121(6), 859–872. https://doi.org/10.1016/j.cell.2005.03.036

    Article  CAS  PubMed  Google Scholar 

  64. Koche, R. P., Smith, Z. D., Adli, M., et al. (2011). Reprogramming factor expression initiates widespread targeted chromatin remodeling. Cell Stem Cell, 8(1), 96–105. https://doi.org/10.1016/j.stem.2010.12.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Dabiri, Y., Gama-Brambila, R. A., Taškova, K., et al. (2019). Imidazopyridines as potent KDM5 demethylase inhibitors promoting reprogramming efficiency of human iPSCs. iScience, 12, 168–181. https://doi.org/10.1016/j.isci.2019.01.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Ringrose, L., Ehret, H., & Paro, R. (2004). Distinct contributions of histone H3 lysine 9 and 27 methylation to locus-specific stability of polycomb complexes. Molecular Cell, 16(4), 641–653. https://doi.org/10.1016/j.molcel.2004.10.015

    Article  CAS  PubMed  Google Scholar 

  67. Francis, N. J., Kingston, R. E., & Woodcock, C. L. (2004). Chromatin compaction by a polycomb group protein complex. Science, 306(5701), 1574–1577. https://doi.org/10.1126/science.1100576

    Article  CAS  PubMed  Google Scholar 

  68. Liber, D., Domaschenz, R., Holmqvist, P. H., et al. (2010). Epigenetic priming of a pre-B cell-specific enhancer through binding of Sox2 and Foxd3 at the ESC stage. Cell Stem Cell, 7(1), 114–126. https://doi.org/10.1016/j.stem.2010.05.020

    Article  CAS  PubMed  Google Scholar 

  69. Relaix, F., Rocancourt, D., Mansouri, A., et al. (2005). A Pax3/Pax7-dependent population of skeletal muscle progenitor cells. Nature, 435(7044), 948–953. https://doi.org/10.1038/nature03594

    Article  CAS  PubMed  Google Scholar 

  70. Kidder, B. L., Hu, G., Yu, Z. X., et al. (2013). Extended self-renewal and accelerated reprogramming in the absence of Kdm5b. Molecular and Cellular Biology, 33(24), 4793–4810. https://doi.org/10.1128/mcb.00692-13

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Xhabija, B., & Kidder, B. L. (2019). KDM5B is a master regulator of the H3K4-methylome in stem cells, development and cancer. Seminars in Cancer Biology, 57, 79–85. https://doi.org/10.1016/j.semcancer.2018.11.001

    Article  CAS  PubMed  Google Scholar 

  72. Kim, D., Patel, S. R., Xiao, H., et al. (2009). The role of PTIP in maintaining embryonic stem cell pluripotency. Stem Cells, 27(7), 1516–1523. https://doi.org/10.1002/stem.79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Lohmann, F., Loureiro, J., Su, H., et al. (2010). KMT1E mediated H3K9 methylation is required for the maintenance of embryonic stem cells by repressing trophectoderm differentiation. Stem cells (Dayton, Ohio), 28(2), 201–212. https://doi.org/10.1002/stem.278

    Article  CAS  Google Scholar 

  74. Hattori, N., Imao, Y., Nishino, K., et al. (2007). Epigenetic regulation of Nanog gene in embryonic stem and trophoblast stem cells. Genes to Cells, 12(3), 387–396. https://doi.org/10.1111/j.1365-2443.2007.01058.x

    Article  CAS  PubMed  Google Scholar 

  75. Wang, H., An, W., Cao, R., et al. (2003). mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional repression. Molecular Cell, 12(2), 475–487. https://doi.org/10.1016/j.molcel.2003.08.007

    Article  CAS  PubMed  Google Scholar 

  76. Topalovic, V., Schwirtlich, M., Stevanovic, M., et al. (2017). Histone modifications on the promoters of human OCT4 and NANOG genes at the onset of neural differentiation of NT2/D1 cells. Biochemistry (Moscow), 82(6), 715–722. https://doi.org/10.1134/s0006297917060086

    Article  CAS  Google Scholar 

  77. Chou, R. H., Yu, Y. L., & Hung, M. C. (2011). The roles of EZH2 in cell lineage commitment. American Journal of Translation Research, 3(3), 243–250.

    CAS  Google Scholar 

  78. James, A. W., Pang, S., Askarinam, A., et al. (2012). Additive effects of sonic hedgehog and Nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells. Stem Cells and Development, 21(12), 2170–2178. https://doi.org/10.1089/scd.2011.0461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pei, L., & Tontonoz, P. (2004). Fat’s loss is bone’s gain. The Journal of Clinical Investigation, 113(6), 805–806. https://doi.org/10.1172/jci21311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Diao, S., Yang, D. M., Dong, R., et al. (2015). Enriched trimethylation of lysine 4 of histone H3 of WDR63 enhanced osteogenic differentiation potentials of stem cells from apical papilla. Journal of Endodontia, 41(2), 205–211. https://doi.org/10.1016/j.joen.2014.09.027

    Article  Google Scholar 

  81. He, S., Yang, S., Zhang, Y., et al. (2019). LncRNA ODIR1 inhibits osteogenic differentiation of hUC-MSCs through the FBXO25/H2BK120ub/H3K4me3/OSX axis. Cell Death & Disease, 10(12), 947. https://doi.org/10.1038/s41419-019-2148-2

    Article  CAS  Google Scholar 

  82. Rojas, A., Aguilar, R., Henriquez, B., et al. (2015). Epigenetic control of the bone-master runx2 gene during osteoblast-lineage commitment by the histone demethylase JARID1B/KDM5B. Journal of Biological Chemistry, 290(47), 28329–28342. https://doi.org/10.1074/jbc.M115.657825

    Article  CAS  Google Scholar 

  83. Wu, H., Gordon, J. A., Whitfield, T. W., et al. (1860). (2017) Chromatin dynamics regulate mesenchymal stem cell lineage specification and differentiation to osteogenesis. Biochimica et Biophysica Acta, Gene Regulatory Mechanisms, 4, 438–449. https://doi.org/10.1016/j.bbagrm.2017.01.003

    Article  CAS  Google Scholar 

  84. Zhang, X., Wang, W., Wang, Y., et al. (2020). Extracellular vesicle-encapsulated miR-29b-3p released from bone marrow-derived mesenchymal stem cells underpins osteogenic differentiation. Frontiers in Cell and Development Biology, 8, 581545. https://doi.org/10.3389/fcell.2020.581545

    Article  Google Scholar 

  85. Guo, L., Guo, Y. Y., Li, B. Y., et al. (2019). Histone demethylase KDM5A is transactivated by the transcription factor C/EBPβ and promotes preadipocyte differentiation by inhibiting Wnt/β-catenin signaling. Journal of Biological Chemistry, 294(24), 9642–9654. https://doi.org/10.1074/jbc.RA119.008419

    Article  CAS  Google Scholar 

  86. Hemming, S., Cakouros, D., Isenmann, S., et al. (2014). EZH2 and KDM6A act as an epigenetic switch to regulate mesenchymal stem cell lineage specification. Stem Cells, 32(3), 802–815. https://doi.org/10.1002/stem.1573

    Article  CAS  PubMed  Google Scholar 

  87. Isenmann, S., Arthur, A., Zannettino, A. C., et al. (2009). TWIST family of basic helix-loop-helix transcription factors mediate human mesenchymal stem cell growth and commitment. Stem Cells, 27(10), 2457–2468. https://doi.org/10.1002/stem.181

    Article  CAS  PubMed  Google Scholar 

  88. Hemming, S., Cakouros, D., Vandyke, K., et al. (2016). Identification of novel EZH2 targets regulating osteogenic differentiation in mesenchymal stem cells. Stem Cells Dev, 25(12), 909–921. https://doi.org/10.1089/scd.2015.0384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Stachecka, J., Kolodziejski, P. A., Noak, M., et al. (2021). Alteration of active and repressive histone marks during adipogenic differentiation of porcine mesenchymal stem cells. Science and Reports, 11(1), 1325. https://doi.org/10.1038/s41598-020-79384-x

    Article  CAS  Google Scholar 

  90. Liu, F., Song, D. Y., Huang, J., et al. (2021). Long non-coding RNA CIR inhibits chondrogenic differentiation of mesenchymal stem cells by epigenetically suppressing ATOH8 via methyltransferase EZH2. Molecular Medicine, 27(1), 12. https://doi.org/10.1186/s10020-021-00272-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Takada, I., Kouzmenko, A. P., & Kato, S. (2009). Molecular switching of osteoblastogenesis versus adipogenesis: Implications for targeted therapies. Expert Opinion on Therapeutic Targets, 13(5), 593–603. https://doi.org/10.1517/14728220902915310

    Article  CAS  PubMed  Google Scholar 

  92. Ye, L., Fan, Z., Yu, B., et al. (2012). Histone demethylases KDM4B and KDM6B promotes osteogenic differentiation of human MSCs. Cell Stem Cell, 11(1), 50–61. https://doi.org/10.1016/j.stem.2012.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wróblewski, A., Strycharz, J., Świderska, E., et al. (2021). Chronic and Transient hyperglycemia induces changes in the expression patterns of IL6 and ADIPOQ genes and their associated epigenetic modifications in differentiating human visceral adipocytes. International Journal of Molecular Sciences, 22(13), 6964. https://doi.org/10.3390/ijms22136964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Völker-Albert, M., Bronkhorst, A., Holdenrieder, S., et al. (2020). Histone modifications in stem cell development and their clinical implications. Stem Cell Reports, 15(6), 1196–1205. https://doi.org/10.1016/j.stemcr.2020.11.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kampilafkos, P., Melachrinou, M., Kefalopoulou, Z., et al. (2015). Epigenetic modifications in cutaneous malignant melanoma: EZH2, H3K4me2, and H3K27me3 immunohistochemical expression is enhanced at the invasion front of the tumor. American Journal of Dermatopathology, 37(2), 138–144. https://doi.org/10.1097/DAD.0b013e31828a2d54

    Article  Google Scholar 

  96. Lin, B., Lee, H., Yoon, J. G., et al. (2015). Global analysis of H3K4me3 and H3K27me3 profiles in glioblastoma stem cells and identification of SLC17A7 as a bivalent tumor suppressor gene. Oncotarget, 6(7), 5369–5381. https://doi.org/10.18632/oncotarget.3030

    Article  PubMed  PubMed Central  Google Scholar 

  97. Xiu, M., Wang, Y., Li, B., et al. (2021). The role of Notch3 signaling in cancer stemness and chemoresistance: Molecular mechanisms and targeting strategies. Frontiers in Molecular Biosciences, 8, 694141. https://doi.org/10.3389/fmolb.2021.694141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Chen, C., Ma, Z., & Jiang, H. (2021). EMT participates in the regulation of exosomes secretion and function in esophageal cancer cells. Technology in Cancer Research & Treatment, 20, 15330338211033076. https://doi.org/10.1177/15330338211033077

    Article  CAS  Google Scholar 

  99. Li, Q., O’malley, M. E., Bartlett, D. L., et al. (2011). Homeobox gene Rhox5 is regulated by epigenetic mechanisms in cancer and stem cells and promotes cancer growth. Molecular Cancer, 10, 63. https://doi.org/10.1186/1476-4598-10-63

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Mani, S. A., Guo, W., Liao, M. J., et al. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133(4), 704–715. https://doi.org/10.1016/j.cell.2008.03.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wang, H., & Unternaehrer, J. J. (2019). Epithelial-mesenchymal transition and cancer stem cells: At the crossroads of differentiation and dedifferentiation. Developmental Dynamics, 248(1), 10–20. https://doi.org/10.1002/dvdy.24678

    Article  PubMed  Google Scholar 

  102. Van Haaften, G., Dalgliesh, G. L., Davies, H., et al. (2009). Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nature Genetics, 41(5), 521–523. https://doi.org/10.1038/ng.349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Gui, Y., Guo, G., Huang, Y., et al. (2011). Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nature Genetics, 43(9), 875–878. https://doi.org/10.1038/ng.907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Dalgliesh, G. L., Furge, K., Greenman, C., et al. (2010). Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature, 463(7279), 360–363. https://doi.org/10.1038/nature08672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lee, E., Wang, J., Yumoto, K., et al. (2016). DNMT1 regulates epithelial-mesenchymal transition and cancer stem cells, which promotes prostate cancer metastasis. Neoplasia (New York, N.Y.), 18(9), 553–566. https://doi.org/10.1016/j.neo.2016.07.007

    Article  CAS  Google Scholar 

  106. Tan, X., Chen, S., Wu, J., et al. (2017). PI3K/AKT-mediated upregulation of WDR5 promotes colorectal cancer metastasis by directly targeting ZNF407. Cell Death & Disease, 8(3), e2686. https://doi.org/10.1038/cddis.2017.111

    Article  CAS  Google Scholar 

  107. Shen, C., Yan, T., Tong, T., et al. (2020). ALKBH4 functions as a suppressor of colorectal cancer metastasis via competitively binding to WDR5. Front Cell Dev Biol, 8, 293. https://doi.org/10.3389/fcell.2020.00293

    Article  PubMed  PubMed Central  Google Scholar 

  108. Wang, F., Zhang, J., Ke, X., et al. (2020). WDR5-Myc axis promotes the progression of glioblastoma and neuroblastoma by transcriptional activating CARM1. Biochemical and Biophysical Research Communications, 523(3), 699–706. https://doi.org/10.1016/j.bbrc.2019.12.101

    Article  CAS  PubMed  Google Scholar 

  109. Zhang, P., Zhang, Y., Mao, L., et al. (2009). Side population in oral squamous cell carcinoma possesses tumor stem cell phenotypes. Cancer Letters, 277(2), 227–234. https://doi.org/10.1016/j.canlet.2008.12.015

    Article  CAS  PubMed  Google Scholar 

  110. Lindner, P., Paul, S., Eckstein, M., et al. (2020). EMT transcription factor ZEB1 alters the epigenetic landscape of colorectal cancer cells. Cell Death & Disease, 11(2), 147. https://doi.org/10.1038/s41419-020-2340-4

    Article  CAS  Google Scholar 

  111. Kanayama, K., Chiba, T., Oshima, M., et al. (2019). Genome-wide mapping of bivalent histone modifications in hepatic stem/progenitor cells. Stem Cells International, 2019, 9789240. https://doi.org/10.1155/2019/9789240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Xu, C. R., Cole, P. A., Meyers, D. J., et al. (2011). Chromatin “prepattern” and histone modifiers in a fate choice for liver and pancreas. Science (New York, N.Y.), 332(6032), 963–966. https://doi.org/10.1126/science.1202845

    Article  CAS  Google Scholar 

  113. Chiba, T., Seki, A., Aoki, R., et al. (2010). Bmi1 promotes hepatic stem cell expansion and tumorigenicity in both Ink4a/Arf-dependent and -independent manners in mice. Hepatology, 52(3), 1111–1123. https://doi.org/10.1002/hep.23793

    Article  CAS  PubMed  Google Scholar 

  114. Ezhkova, E., Pasolli, H. A., Parker, J. S., et al. (2009). Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells. Cell, 136(6), 1122–1135. https://doi.org/10.1016/j.cell.2008.12.043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Mochizuki-Kashio, M., Mishima, Y., Miyagi, S., et al. (2011). Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells. Blood, 118(25), 6553–6561. https://doi.org/10.1182/blood-2011-03-340554

    Article  CAS  PubMed  Google Scholar 

  116. Murdaugh, R. L., Hoegenauer, K. A., Kitano, A., et al. (2021). The histone H3.3 chaperone HIRA restrains erythroid-biased differentiation of adult hematopoietic stem cells. Stem Cell Reports. https://doi.org/10.1016/j.stemcr.2021.06.009

    Article  PubMed  PubMed Central  Google Scholar 

  117. Lee, G. R. (2018). The balance of Th17 versus Treg cells in autoimmunity. International Journal of Molecular Sciences, 19(3), 730. https://doi.org/10.3390/ijms19030730

    Article  CAS  PubMed Central  Google Scholar 

  118. Thomas, R. M., Sai, H., & Wells, A. D. (2012). Conserved intergenic elements and DNA methylation cooperate to regulate transcription at the il17 locus. Journal of Biological Chemistry, 287(30), 25049–25059. https://doi.org/10.1074/jbc.M112.351916

    Article  CAS  Google Scholar 

  119. Cribbs, A. P., Terlecki-Zaniewicz, S., Philpott, M., et al. (2020). Histone H3K27me3 demethylases regulate human Th17 cell development and effector functions by impacting on metabolism. Proceedings of National Academy of Sciences of the United States of America, 117(11), 6056–6066. https://doi.org/10.1073/pnas.1919893117

    Article  CAS  Google Scholar 

  120. Chen, Q., Duan, X., Xu, M., et al. (2020). BMSC-EVs regulate Th17 cell differentiation in UC via H3K27me3. Molecular Immunology, 118, 191–200. https://doi.org/10.1016/j.molimm.2019.12.019

    Article  CAS  PubMed  Google Scholar 

  121. Pereira, R. M., Martinez, G. J., Engel, I., et al. (2014). Jarid2 is induced by TCR signalling and controls iNKT cell maturation. Nature Communications, 5, 4540. https://doi.org/10.1038/ncomms5540

    Article  CAS  PubMed  Google Scholar 

  122. Xiao, X., Shi, X., Fan, Y., et al. (2016). The costimulatory receptor OX40 inhibits interleukin-17 expression through activation of repressive chromatin remodeling pathways. Immunity, 44(6), 1271–1283. https://doi.org/10.1016/j.immuni.2016.05.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Adoue, V., & Joffre, O. (2020). Endogenous retroviruses: Friend or foe of the immune system? Medecine Sciences : M/S, 36(3), 253–260. https://doi.org/10.1051/medsci/2020022

    Article  Google Scholar 

  124. Kaleviste, E., Saare, M., Leahy, T. R., et al. (2019). Interferon signature in patients with STAT1 gain-of-function mutation is epigenetically determined. European Journal of Immunology, 49(5), 790–800. https://doi.org/10.1002/eji.201847955

    Article  CAS  PubMed  Google Scholar 

  125. Lin, F., Meng, X., Guo, Y., et al. (2019). Epigenetic initiation of the T(H)17 differentiation program is promoted by Cxxc finger protein 1. Sciences Advances, 5(10), eaax1608. https://doi.org/10.1126/sciadv.aax1608

    Article  CAS  Google Scholar 

  126. Li, Q., Zou, J., Wang, M., et al. (2014). Critical role of histone demethylase Jmjd3 in the regulation of CD4+ T-cell differentiation. Nature Communications, 5, 5780. https://doi.org/10.1038/ncomms6780

    Article  CAS  PubMed  Google Scholar 

  127. Liu, X., Ren, S., Qu, X., et al. (2015). Mesenchymal stem cells inhibit Th17 cells differentiation via IFN-γ-mediated SOCS3 activation. Immunologic Research, 61(3), 219–229. https://doi.org/10.1007/s12026-014-8612-2

    Article  CAS  PubMed  Google Scholar 

  128. Mi, Q. S., Wang, J., Liu, Q., et al. (2021). microRNA dynamic expression regulates invariant NKT cells. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-021-03895-7

    Article  PubMed  Google Scholar 

  129. Dobenecker, M. W., Kim, J. K., Marcello, J., et al. (2015). Coupling of T cell receptor specificity to natural killer T cell development by bivalent histone H3 methylation. Journal of Experimental Medicine, 212(3), 297–306. https://doi.org/10.1084/jem.20141499

    Article  CAS  Google Scholar 

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (Grant No. 31201052). The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.

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This study was funded by the National Natural Science Foundation of China (Grant No. 31201052). The authors confirm independence from the sponsors; the content of the article has not been influenced by the sponsors.

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  1. Han Sun, Yin Wang, Ying Wang, Feng Ji and An Wang contributed equally to this study.

Authors and Affiliations

  1. The Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China

    Han Sun, Yin Wang, Ying Wang, Feng Ji, An Wang, Xu He & Lisha Li

  2. Department of Molecular Biology, College of Basic Medical Sciences, Jilin University, Changchun, 130021, China

    Ming Yang

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Han Sun, Feng Ji, Ying Wang and An Wang participated in the writing. Han Sun, Ying Wang and Feng Ji designed and prepared the figures. An Wang and Han Sun designed and prepared the tables. Yin Wang and Xu He were in charge of proofreading manuscripts. Lisha Li, Xu He and Ming Yang designed and polished the paper.

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Sun, H., Wang, Y., Wang, Y. et al. Bivalent Regulation and Related Mechanisms of H3K4/27/9me3 in Stem Cells. Stem Cell Rev and Rep 18, 165–178 (2022). https://doi.org/10.1007/s12015-021-10234-7

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