DNA methylation is an epigenetic modification associated with transcriptional repression of promoters and is essential for mammalian development. Establishment of DNA methylation is mediated by the de novo DNA methyltransferases DNMT3A and DNMT3B, whereas DNMT1 ensures maintenance of methylation through replication. Absence of these enzymes is lethal, and somatic mutations in these genes have been associated with several human diseases. How genomic DNA methylation patterns are regulated remains poorly understood, as the mechanisms that guide recruitment and activity of DNMTs in vivo are largely unknown. To gain insights into this matter we determined genomic binding and site-specific activity of the mammalian de novo DNA methyltransferases DNMT3A and DNMT3B. We show that both enzymes localize to methylated, CpG-dense regions in mouse stem cells, yet are excluded from active promoters and enhancers. By specifically measuring sites of de novo methylation, we observe that enzymatic activity reflects binding. De novo methylation increases with CpG density, yet is excluded from nucleosomes. Notably, we observed selective binding of DNMT3B to the bodies of transcribed genes, which leads to their preferential methylation. This targeting to transcribed sequences requires SETD2-mediated methylation of lysine 36 on histone H3 and a functional PWWP domain of DNMT3B. Together these findings reveal how sequence and chromatin cues guide de novo methyltransferase activity to ensure methylome integrity.

Genomic profiling of DNA methyltransferases reveals a role for DNMT3B in genic methylation

https://www.cell.com/cancer-cell/pdf/S1535-6108(15)00346-3.pdf

Inhibiting WEE1 Selectively Kills Histone H3K36me3-Deficient Cancers by dNTP Starvation.

Methyltransferase SETD2-Mediated Methylation of STAT1 Is Critical for Interferon Antiviral Activity

The Biogenesis and Precise Control of RNA m6A Methylation

Methylation of cytosines (5(me)C) is a widespread heritable DNA modification. During mammalian development, two global demethylation events are followed by waves of de novo DNA methylation. In vivo mechanisms of DNA methylation establishment are largely uncharacterized. Here, we use Saccharomyces cerevisiae as a system lacking DNA methylation to define the chromatin features influencing the activity of the murine DNMT3B. Our data demonstrate that DNMT3B and H3K4 methylation are mutually exclusive and that DNMT3B is co-localized with H3K36 methylated regions. In support of this observation, DNA methylation analysis in yeast strains without Set1 and Set2 shows an increase of relative 5(me)C levels at the transcription start site and a decrease in the gene-body, respectively. We extend our observation to the murine male germline, where H3K4me3 is strongly anti-correlated while H3K36me3 correlates with accelerated DNA methylation. These results show the importance of H3K36 methylation for gene-body DNA methylation in vivo.

/pdf/in-vivo-targeting-of-de-novo-dna-methylation-by-histone-1uuepemt57.pdf

In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse

https://cyberleninka.org/article/n/571550.pdf

H3K36 Histone Methyltransferase Setd2 Is Required for Murine Embryonic Stem Cell Differentiation toward Endoderm

Modal parameter identification using response data only

Dynamic behavior and sound transmission analysis of a fluid–structure coupled system using the direct-BEM/FEM

The stable or metastable phase was found to be dependent on the size of ZrO 2 nano particles. Amorphous hydrated ZrO 2 powders prepared by precipitation were annealed at 1300 °C and maintained for different length of time followed by being quenched in ambient. The average particle size and phases were determined by X-ray diffraction cross-checked by transmission electron microscopy. The powders were found composed of monoclinic (m) phase when the particle size ( d ) is larger than 31 nm, whereas tetragonal (t) phase remains stable at room temperature when particle size is less than 14 nm. The mixture of the t and m phases is observed when average particle size locates between 14 and 31 nm. Thermodynamic calculation indicates that the surface free energy difference between tetragonal and monoclinic phases surpasses the volume chemical free energy difference between two phases at room temperature when the particle size of zirconia decreases below 13 nm. The lower surface energy of tetragonal phase results in the stability of tetragonal structure at room temperature, while tetragonal phase is normally stable at high temperature for coarse ceramics. The experimental results are in good agreement with theoretical prediction.

Yuanliang Zhang

Papers

H3K36 Histone Methyltransferase Setd2 Is Required for Murine Embryonic Stem Cell Differentiation toward Endoderm

Modal parameter identification using response data only

Dynamic behavior and sound transmission analysis of a fluid–structure coupled system using the direct-BEM/FEM

The size dependence of structural stability in nano-sized ZrO2 particles

On the t → m martensitic transformation in Ce–Y-TZP ceramics