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DNA methylation pathways and their crosstalk with histone methylation

Key Points

  • DNA methylation is highly correlated with the histone H3K9me mark in silenced genes from fungi to human.

  • DNA methylation and H3K9me marks crosstalk with each other through certain structural domains that specifically recognize methylated DNA and histones.

  • The fungi Neurospora crassa has a unidirectional regulation pathway from histone to DNA methylation.

  • Recent structural and functional studies have uncovered the complex cross regulatory network between DNA and histone methylation in the model plant Arabidopsis thaliana.

  • In mammals, multiple pathways are involved in both de novo and maintenance DNA methylation linking unmethylated H3K4, H3K9me and H3K36me to various targeting mechanisms.

Abstract

Methylation of DNA and of histone 3 at Lys 9 (H3K9) are highly correlated with gene silencing in eukaryotes from fungi to humans. Both of these epigenetic marks need to be established at specific regions of the genome and then maintained at these sites through cell division. Protein structural domains that specifically recognize methylated DNA and methylated histones are key for targeting enzymes that catalyse these marks to appropriate genome sites. Genetic, genomic, structural and biochemical data reveal connections between these two epigenetic marks, and these domains mediate much of the crosstalk.

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Figure 1: A unidirectional pathway in Neurospora crassa.
Figure 2: Structural basis underlying the cross-regulation of CHG DNA methylation and histone H3K9me2 in Arabidopsis thaliana by the self-reinforcing loop between CMT3 and KRYPTONITE.
Figure 3: Structures of regulators of Arabidopsis thaliana RdDM pathway.
Figure 4: Structure of mammalian de novo DNA methyltransferases DNMT3A and DNMT3L.
Figure 5: Structures of DNMT1 and its epigenetic regulator UHRF1 in maintenance DNA methylation.

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Acknowledgements

The authors thank W. Pastor and E. Selker for helpful comments on the manuscript. This work was supported by the Chinese Academy of Sciences (to J.D.), NIH grant GM60398 (to S.E.J.), and LLSCOR Program Project and STARR Foundation grants (to D.J.P.). S.E.J. is an investigator of the Howard Hughes Medical Institute.

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FURTHER INFORMATION

RCSB Protein Data Bank

Glossary

Symmetrical sequences

DNA fragments that display the same sequence on both DNA strands.

Asymmetrical sequence

A sequence that is only present on one strand of the DNA.

Readers

Proteins and domains capable of binding to a specific epigenetic mark to recruit certain proteins to the target epigenetic mark.

Chromodomains

A type of reader module that targets histone lysine methylation marks.

Bromo adjacent homology domains

(BAH domains). Another type of reader module that targets histone lysine methylation marks.

Hemimethylated sites

DNA sequences that are methylated on only one of the two complementary DNA strands.

Agrobacterium tumefaciens-mediated transformation

The process of experimentally inserting foreign DNA in the genome of a plant via infiltration with Agrobacterium tumefaciens.

Isothermal Titration Calorimetry

(ITC). A biophysical technique that quantifies the solution interaction features by measuring the reaction thermodynamic changes.

Epiallele

An allele that differs in its epigenetic marks, not in its DNA sequence.

Major satellites

Refers to the 234 bp repeat sequence found in the pericentromeric region in mice.

Minor satellites

Refers to the 120 bp repeat sequences found in the centromeric region in mice.

Retroviruses

RNA viruses that use reverse transcriptase to convert their genome into DNA, which is then integrated into the host genome.

Repetitive element

A sequence that is found in multiple copies in the genome. Examples are telomeric repeats, transposable elements, and centromeric repeats.

Inactive X chromosome

One of the two X chromosomes in females is inactivated to prevent overexpression of X gene products in females compared to males. This silencing is done through formation of heterochromatin.

Primordial germ cell

A Cell that gives rise to both spermatozoa and oocytes.

Retroelements

Transposable elements that move via the transcription of an RNA intermediate.

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Du, J., Johnson, L., Jacobsen, S. et al. DNA methylation pathways and their crosstalk with histone methylation. Nat Rev Mol Cell Biol 16, 519–532 (2015). https://doi.org/10.1038/nrm4043

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