title: Nucleosomes containing methylated DNA stabilize DNA methyltransferases 3A/3B and ensure faithful epigenetic inheritance.
abstract: How epigenetic information is propagated during somatic cell divisions is still unclear but is absolutely critical for preserving gene expression patterns and cellular identity. Here we show an unanticipated mechanism for inheritance of DNA methylation patterns where the epigenetic mark not only recruits the catalyzing enzyme but also regulates the protein level, i.e. the enzymatic product (5-methylcytosine) determines the level of the methylase, thus forming a novel homeostatic inheritance system. Nucleosomes containing methylated DNA stabilize de novo DNA methyltransferases, DNMT3A/3B, allowing little free DNMT3A/3B enzymes to exist in the nucleus. Stabilization of DNMT3A/3B on nucleosomes in methylated regions further promotes propagation of DNA methylation. However, reduction of cellular DNA methylation levels creating more potential CpG substrates counter-intuitively results in a dramatic decrease of DNMT3A/3B proteins due to diminished nucleosome binding and subsequent degradation of the unstable free proteins. These data show an unexpected self-regulatory inheritance mechanism that not only ensures somatic propagation of methylated states by DNMT1 and DNMT3A/3B enzymes but also prevents aberrant de novo methylation by causing degradation of free DNMT3A/3B enzymes.
authors.affiliation: Department of Urology, Biochemistry, and Molecular Biology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: Shikhar
authors.initials: S
authors.lastname: Sharma
authors.forename: Daniel D
authors.initials: DD
authors.lastname: De Carvalho
authors.forename: Shinwu
authors.initials: S
authors.lastname: Jeong
authors.forename: Peter A
authors.initials: PA
authors.lastname: Jones
authors.forename: Gangning
authors.initials: G
authors.lastname: Liang
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004795:Enzyme Stability; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D020868:Gene Silencing; D005822:Genetic Vectors; D045325:HCT116 Cells; D006801:Humans; D009707:Nucleosomes / Q000201:enzymology*; D000097584:DNA Methyltransferase 3B
chemical_list: D044503:5-Methylcytosine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D009707:Nucleosomes; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C000619380:DNMT1 protein, human