聊完DNA甲基化,聊聊DNA去甲基化

文摘   2025-01-01 22:25   德国  

DNA甲基化和去甲基化是表观遗传学中的关键过程,它们在基因表达调控、细胞分化、胚胎发育以及疾病发生中扮演着重要角色。本文将全面介绍DNA去甲基化的机制、功能以及在不同生物学过程中的作用。
DNA去甲基化概述
DNA去甲基化是指DNA上的甲基化修饰被移除的过程,这一过程对于维持基因组稳定性和调控基因表达至关重要。DNA去甲基化可以分为被动去甲基化和主动去甲基化两种类型。被动去甲基化发生在DNA复制过程中,由于甲基化标记未能被复制链继承而逐渐稀释。主动去甲基化则不依赖于DNA复制,而是通过酶促反应直接移除甲基化修饰。
DNA去甲基化的分子机制
Tet酶介导的氧化去甲基化途径

TET(ten-eleven translocation)家族蛋白是DNA主动去甲基化的关键酶,包括TET1、TET2和TET3。这些酶能够氧化5-甲基胞嘧啶(5mC)生成5-羟甲基胞嘧啶(5hmC)、5-醛基胞嘧啶(5fC)和5-羧基胞嘧啶(5caC)。这些3氧化产物可以被胸腺嘧啶DNA糖苷酶(TDG)识别并切除,随后通过碱基切除修复(BER)途径实现DNA的去甲基化。

其他可能的去甲基化途径

除了Tet酶介导的途径外,还存在其他可能的DNA去甲基化机制,如直接移除甲基基团、BER途径直接切除5mC、5mC脱氨-碱基切除修复途径以及核苷酸切除修复途径等。这些途径的具体机制和生物学意义仍需进一步研究。



DNA去甲基化在生物学过程中的作用 
胚胎发育中的DNA去甲基化

在小鼠胚胎发育过程中,基因组会发生两次大规模去甲基化,分别在受精后和配子形成过程中。这些去甲基化过程对于基因组重编程和胚胎发育至关重要。

细胞分化与DNA去甲基化

在细胞分化过程中,特定基因的去甲基化与基因激活相关,而甲基化则与基因沉默相关。TET酶和5hmC水平的变化与细胞多能性和分化状态密切相关。

衰老与DNA去甲基化

随着衰老,全基因组或特定位点的DNA甲基化水平会发生改变,这些改变与衰老相关疾病的发展有关。

肿瘤与DNA去甲基化
TET酶的突变与某些类型的肿瘤发生有关。此外,肿瘤细胞中维生素C含量的降低可能会影响TET酶的活性,进而影响DNA主动去甲基化过程。

参考文献

  1. Goll, M. G. & Bestor, T. H. Eukaryotic cytosine methyltransferases. Annu. Rev. Biochem 74, 481-514 (2005).
  2. Okano, M. et al. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247-257 (1999).
  3. Okano, M. et al. Dnmt2 is not required for de novo and maintenance methylation of viral DNA in embryonic stem cells. Nucleic Acids Res. 26, 2536-2540 (1998).
  4. Bestor, T. et al. Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. J. Mol. Biol. 203, 971-983 (1988).
  5. Ooi, S. K. & Bestor, T. H. The colorful history of active DNA demethylation. Cell 133, 1145-1148 (2008).
  6. Rick, W. Stability and flexibility of epigenetic gene regulation in mammalian development: Nature 447, 425-432 (2007).
  7. Rick, W. et al. Epigenetic reprogramming in mammalian development. Science 293, 1089-1093 (2001).
  8. Gu, T. P. et al. The role of Tet3 DNA dioxygenase in epigenetic reprogramming by oocytes. Nature 477, 606-610 (2011).
  9. Kishigami, S. et al. Epigenetic abnormalities of the mouse paternal zygotic genome associated with microinsemination of round spermatids. Dev. Biol. 289, 195-205 (2006).
  10. Guo, F. et al. Active and passive demethylation of male and female pronuclear DNA in the mammalian zygote. Cell Stem Cell 15, 447-459 (2014).
  11. Shen, L. et al. Tet3 and DNA replication mediate demethylation of both the maternal and paternal genomes in mouse zygotes. Cell Stem Cell 15, 459-470 (2014).
  12. Hashimoto, H. et al. Recognition and potential mechanisms for replication and erasure of cytosine hydroxymethylation. Nucleic Acids Res. 40, 4841-4849 (2012).
  13. Ramchandani, S. et al. DNA methylation is a reversible biological signal. Proc. Natl. Acad. Sci. U.S.A. 96, 6107-6112 (1999).
  14. Wu, J. C. & Santi, D. V. Kinetic and catalytic mechanism of HhaI methyltransferase. J. Biol. Chem. 262, 4778-4786 (1987).
  15. Liutkeviciute, Z. et al. Direct Decarboxylation of 5-Carboxyleytosine by DNA C5-Methyltransferases. J. Am. Chem. Soc. 136, 5884-5887 (2014).
  16. Agius, F. et al. Role of the Arabidopsis DNA glycosylase/lyase ROS1 in active DNA demethylation. Proc. Natl. Acad. Sci. U.S.A. 103, 11796-11801 (2006).
  17. Gehring, M. et al. Demeter DNA glycosylase establishes medea polycomb gene self-imprinting by allele-specific demethylation. Cell 124, 495-506 (2006).
  18. Morales-Ruiz, T. et al. Demeter and repressor of silencing 1 encode 5-methylcytosine DNA glycosylases. Proc. Natl. Acad. Sci. U.S.A. 103, 6853-6858 (2006).
  19. Conticello, S. G. The AID/APOBEC family of nucleic acid mutators. Genome Biol. 9, 229 (2008).
  20. Wu, X. & Zhang, Y. TET-mediated active DNA demethylation: mechanism, function and beyond. Nat. Rev. Genet. 18, 517-534 (2017).

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