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Genomic profiling of DNA
methyltransferases reveals
a role for DNMT3B in genic methylation
Tuncay Baubec, Daniele F. Colombo, Christiane Wirbelauer, Juliane Schmidt1, Lukas Burger, Arnaud R. Krebs,
Altuna Akalin & Dirk Schubeler
De novo methylation and maintenance methylation of DNA
E. Li and Y. Zhang , Harb Perspect Biol 2014
Function of mammalian DNA methyltransferases
DNA methyltransferase
Species
Major activity
Major phenotypes of loss of function
Dnmt1
Mouse
Maintenance methylation of CpG
Genome-wide loss of DNA methylation, embryonic lethality at
embryonic day 9.5 (E9.5), abnormal expression of imprinted
genes, ectopic X-chromosome inactivation, activation of silent
retrotransposon. In cancer cell lines, it leads to cell cycle arrest
and mitotic defects.
Dnmt3a
Mouse
De novo methylation of CpG
Postnatal lethality at 4–8 wk, male sterility, and failure to establish
methylation imprints in both male and female germ cells
Dnmt3b
Mouse
De novo methylation of CpG
Demethylation of minor satellite DNA, embryonic lethality around
E14.5 days with vascular and liver defects. (Embryos lacking both
Dnmt3a and Dnmt3b fail to initiate de novo methylation after
implantation and die at E9.5.)
DNMT3B
Human
De novo methylation of CpG
ICF syndrome: immunodeficiency, centromeric instability, and
facial anomalies. Loss of methylation in repetitive elements and
pericentromeric heterochromatin.
E. Li and Y. Zhang , Harb Perspect Biol 2014
Mammalian DNA methyltransferases.
PWWP: a highly conserved “proline-tryptophan-tryptophan-proline” motif involved in heterochromatin association
ATRX: a cysteine-rich region containing a zinc finger and PHD domain implicated in protein–protein interactions
E. Li and Y. Zhang , Harb Perspect Biol 2014
Proposed models of DNMT targeting
• How genomic DNA methylation patterns are regulated remains poorly understood
Proposed models:
1. Readout of histone modifications
2. Binding to nucleosomes
3. recruitment by accessory proteins
4. RNA-mediated or DNA sequence-specific targeting or repulsion
Biotin tagging of DNMT3A2 and DNMT3B1 in mouse embryonic stem cells
DNMT3A2 and DNMT3B1 show similar localization to most parts of the
genome, but are differently recruited to gene bodies.
De novo methylation relative to DNMT binding and chromatin features
De novo methylation relative to DNMT binding and chromatin features
Methylation analysis at selected sites indicates a role for DNMT3B in methylation
fidelity at transcribed genes
DNMT3B binding follows co-transcriptional deposition of H3K36me3
The H3K36 methyltransferase SETD2 is required for targeting de novo
methylation to transcribed
Setd2: mediates H3K36me3 methylation at active genes
The PWWP domain of DNMT3B is required for targeting de novo
methylation to transcribed
Mutations in the PWWP domain of DNMT3B1
S277P: ICF syndrome-related mutation in the PWWP domain
leads to loss of binding at active gene bodies
Conclusion
• Deferential binding and methylation patterns
- DNMT3B1 and DMT3A2
• DNMT3B1 recruitment to active genes via H3K36me3 levels
- de novo methylation of active genes
- suggesting a direct requirement for H3K36me3