H3K36me2/3 binding and DNA binding of the DNA methyltransferase DNMT3A PWWP domain both contribute to its chromatin interaction.

@article{Dukatz2019H3K36me23BA,
  title={H3K36me2/3 binding and DNA binding of the DNA methyltransferase DNMT3A PWWP domain both contribute to its chromatin interaction.},
  author={Michael Dukatz and Katharina Holzer and Michel Choudalakis and Max Emperle and Cristiana Lungu and Pavel Bashtrykov and Albert Jeltsch},
  journal={Journal of molecular biology},
  year={2019}
}

Methylation of recombinant mononucleosomes by DNMT3A demonstrates efficient linker DNA methylation and a role of H3K36me3

An evolutionary model is proposed in which the direct stimulatory effect of H3K36me3 on DNA methylation preceded its signaling function, which could explain the evolutionary origin of the widely distributed “active gene body-H3K 36me3-DNA methylation” connection.

Structure of nucleosome-bound DNA methyltransferases DNMT3A and DNMT3B

CpG methylation by de novo DNA methyltransferases 3A and 3B is essential for mammalian development and differentiation and is frequently dysregulated in cancer, and the steric constraints of this arrangement suggest that nucleosomal DNA must be moved relative to the nucleosome core for de noVO methylation to occur.

The DNMT3A PWWP domain is essential for the normal DNA methylation landscape in mouse somatic cells and oocytes

It is revealed that the DNMT3A PWWP domain is important for suppressing aberrant CG hypermethylation in both somatic cells and oocytes but that D329A mutation has little impact on the developmental potential of oocytes.

Structural and functional specificity of H3K36 methylation

The mechanisms that underlie the cooperation between H3K36me and other Chromatin modifications and other chromatin modifications in the physiological regulation of the epigenomic functions of chromatin are discussed.

Two competing mechanisms of DNMT3A recruitment regulate the dynamics of de novo DNA methylation at PRC1-targeted CpG islands.

This study implies that a balance between DNMT3A recruitment by distinct reader domains guides de novo CpG methylation and may underlie the abnormal DNA methylation landscapes observed in select human cancer subtypes and developmental disorders.

Structure of DNA methyltransferases DNMT3A/DNMT3B bound to a nucleosome

The steric constraints of this arrangement suggest that nucleosomal DNA must be moved relative to the nucleosome core for de novo methylation to occur.

NSD1-deposited H3K36me2 directs de novo methylation in the mouse male germline and counteracts Polycomb-associated silencing

It is shown here that SETD2 is dispensable for de novo DNAme in the male germline, and that NSD1, which deposits H3K36me2, is a major regulator of DNA methylation in male but not in female gametogenesis.

Base editor scanning charts the DNMT3A activity landscape

This work integrates base editing with a DNA methylation reporter to perform in situ mutational scanning of DNMT3A in cells and finds mutations throughout the protein that perturb function, including ones at an interdomain interface that block allosteric activation.

Interplay between chromatin marks in development and disease.

The impact of genetic perturbation of the relevant methyltransferases in the mouse on the landscape of chromatin marks as well as the transcriptome is described and the specific neurodevelopmental growth syndromes and cancers resulting from pathogenic mutations in the human orthologues of these genes are discussed.

References

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The Dnmt3a PWWP Domain Reads Histone 3 Lysine 36 Trimethylation and Guides DNA Methylation*

The PWWP-H3K36me3 interaction increases the activity of Dnmt3a for methylation of nucleosomal DNA as observed using native nucleosomes isolated from human cells after demethylation of the DNA with 5-aza-2′-deoxycytidine as substrate for methylated DNA.

Nucleosomal DNA binding drives the recognition of H3K36-methylated nucleosomes by the PSIP1-PWWP domain

Concerted binding to the methylated histone tail and nucleosomal DNA underlies the high- affinity, specific recognition of H3K36me nucleosomes by the PSIP1-PWWP domain.

A DNMT3A PWWP mutation leads to methylation of bivalent chromatin and growth retardation in mice

A mouse model carrying a D329A point mutation in the DNMT3A PWWP domain is presented and it is found this causes dominant postnatal growth retardation, with aberrant progressive gain of DNA methylation across domains marked by H3K27me3 in adult tissues.

The PWWP Domain of Dnmt3a and Dnmt3b Is Required for Directing DNA Methylation to the Major Satellite Repeats at Pericentric Heterochromatin

Evidence is provided that the PWWP domains of Dnmt3a and DnMT3b are involved in functional specialization of these enzymes to pericentric heterochromatin, probably via a mechanism other than protein-DNA interactions.

The PWWP domain of mammalian DNA methyltransferase Dnmt3b defines a new family of DNA-binding folds

The PWWP domain alone binds DNA in vitro, probably through its basic surface, and it is shown that recombinant Dnmt3b2 protein and two N-terminal deletion mutants have approximately equal methyl transfer activity on unmethylated and hemimethylated CpG-containing oligonucleotides.

Chromatin Targeting of de Novo DNA Methyltransferases by the PWWP Domain*

The data establish the PWWP domain as a novel chromatin/chromosome-targeting module and suggest that the P WWP-mediated chromatin association is essential for the function of the de novo methyltransferases during development.

Function and disruption of DNA Methyltransferase 3a cooperative DNA binding and nucleoprotein filament formation

Two roles are proposed: either nucleofilament formation could be required for periodic DNA methylation or favorable interactions between Dnmt3a complexes may be needed for the tight packing of DnMT3a at heterochromatic regions.

H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape

A trans-chromatin regulatory pathway is revealed that connects aberrant intergenic CpG methylation to human neoplastic and developmental overgrowth and NSD1-mediated H3K36me2 is required for the recruitment of DNMT3A and maintenance of DNA methylation at intergenic regions.