The mechanism of DNA methylation regulating gene expression

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      (Contributed by Yan Zhuang)

Background

DNA methylation is a commonly existed epigenetic modification inplants and animals, which is essential for the maintenance of genomic stabilityand the regulation of gene expression. The denovo DNA methylation is dependent on Dnmt3a, Dnmt3b and Dnmt3L, whereas itis maintained by Dnmt1 1. Conversely, DNA methylation can be removed by TET1 in mammals2 andROS1 in plants3 indistinct means. The setting and removal of DNA methylation have been wellelucidated, nevertheless, the mechanism underlying how DNA methylationregulates gene expression still remains largely unknown4. Questions includes how DNA methylation is interpreted and of whichwhat functions downstream.

Interferencein TFs binding to promoters

DNA methylation is mainly distributed in GC-poor promoters andactively expressed gene body regions, whereas not in CpG islands4. Some TFs are unable to bind their target sites when these sites aremethylated. For example, in mice, Igf2and Ins2 are two tandem imprintedgenes expressed in the paternal while silenced in the maternal chromosome. Inthe downstream of the two genes lies a cis-regulatory element ICE, a gene encodinga lncRNA (H19), and a remote enhancer. In the maternal chromosome, a TF namedCTCF binds on ICE to form an insulator between the enhancer and Igf2 and Ins2, consequently prevents the expression of them and activatesthat of the lncRNA. The ICE is methylated on the other chromosome, which interferesthe binding of CTCF on ICE. Therefore, Igf2and Ins2 are activated while H19 issilenced perhaps due to the adjacent DNA methylation5-7 (Fig.1c).

                              

Fig. 1 The impacts of DNA methylation on TFs bindingability

Readersof DNA Methylation

MeCP2 and MBD1-6 harbor a methyl-CpG binding domain, whichrecognizes and binds to methylated DNA without sequence specificity8. MeCP2recruits corepressor Sin3 and histone deacetylation to remodel the chromatinand silence gene expression9,10. Inaddition, other MBDs can associate with corepressor complexes. MBD1 associateswith the Suv39h1-HP1 heterochromatic complex to facilitate histone methylationand repress gene expression11 (Fig.1c). Methyl-CpG-binding protein MeCP2 plays essential roles in neuraldevelopment and its mutation caused Rett syndrome. A recent study reveals thatMeCP2 promotes gene expression by binding to 5hmC in neuronal gene body regions12.

Fig. 2 Mechanism of MBDs directed chromatinremodelling

Perspectives

The mechanism underlying how DNA methylation regulates gene expressionis complex and functional study of an individual molecules is not enoughbecause different proteins form complexes and pathways13. In addition to the description above, some other pioneer TFs canbind to methylated DNA directly and upregulate gene expression8.What’s more, MBDs in plants show little homology with those in mammals outsidethe MBD domain, which means distinct functions of MBDs may exist in plants14.

Reference:

1.  Law, J. A. & Jacobsen, S. E. Establishing,maintaining and modifying DNA methylation patterns in plants and animals. Nat. Rev. Genet. 11, 204-220 (2010).

2.  Tahiliani, M. et al. Conversion of 5-methylcytosineto 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930-935 (2009).

3.  Gong, Z. et al. ROS1, a repressor oftranscriptional gene silencing in Arabidopsis, encodes a DNA glycosylase/lyase.Cell 111, 803-814 (2002).

4.  Schubeler, D. Function andinformation content of DNA methylation. Nature517, 321-326 (2015).

5.  Barlow, D. P. &Bartolomei, M. S. Genomic imprinting in mammals. Cold Spring Harb Perspect Biol 6(2014).

6.  Bell, A. C. & Felsenfeld,G. Methylation of a CTCF-dependent boundary controls imprinted expression ofthe Igf2 gene. Nature 405, 482-485 (2000).

7.  Hark, A. T. et al. CTCF mediatesmethylation-sensitive enhancer-blocking activity at the H19/Igf2 locus. Nature 405, 486-489 (2000).

8.  Zhu, H., Wang, G. &Qian, J. Transcription factors as readers and effectors of DNA methylation. Nat. Rev. Genet. 17, 551-565 (2016).

9.  Nan, X. et al. Transcriptional repression by the methyl-CpG-bindingprotein MeCP2 involves a histone deacetylase complex. Nature 393, 386-389(1998).

10. Jones, P. L. et al. Methylated DNA and MeCP2 recruithistone deacetylase to repress transcription. Nat Genet 19, 187-191(1998).

11. Fujita, N. et al. Methyl-CpG binding domain 1(MBD1) interacts with the Suv39h1-HP1 heterochromatic complex for DNAmethylation-based transcriptional repression. J. Biol. Chem. 278,24132-24138 (2003).

12. Mellen, M., Ayata, P.,Dewell, S., Kriaucionis, S. & Heintz, N. MeCP2 binds to 5hmC enrichedwithin active genes and accessible chromatin in the nervous system. Cell 151, 1417-1430 (2012).

13. Li, E. Chromatinmodification and epigenetic reprogramming in mammalian development. Nat. Rev. Genet. 3, 662-673 (2002).

14. Springer, N. M. &Kaeppler, S. M. Evolutionary divergence of monocot and dicot methyl-CpG-bindingdomain proteins. Plant Physiol. 138, 92-104 (2005).