Li H, Rauch T, Chen ZX, Szabo PE, Riggs AD, Pfeifer GP.. The histone methyltransferase SETDB1 and the DNA methyltransferase DNMT3A interact directly and localize to promoters silenced in cancer cells. J Biol Chem 281: 19489-19500

Division of Biology, Beckman Research Institute, City of Hope, Duarte, California 91010, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 08/2006; 281(28):19489-500. DOI: 10.1074/jbc.M513249200
Source: PubMed


DNA CpG methylation can cooperate with histone H3 lysine 9 (H3-K9) methylation in heterochromatin formation and gene silencing.
Trimethylation of H3-K9 by the recently identified euchromatic histone methyltransferase SETDB1/ESET may be responsible for
transcriptional repression of certain promoters. Here, we show that SETDB1 associates with endogenous DNA methyltransferase
activity. SETDB1 interacts with the de novo DNA methyltransferases DNMT3A and DNMT3B but not with the maintenance methyltransferase DNMT1. The interaction of SETDB1
with DNMT3A was further characterized and confirmed by in vivo and in vitro interaction studies. A direct interaction of the two proteins occurs through the N terminus of SETDB1 and the plant homeodomain
of DNMT3A. Co-expression of SETDB1 and DNMT3A was essential for repression of reporter gene expression in a Gal4-based tethering
assay and resulted in their recruitment to the artificial promoter. We further demonstrate that the CpG-methylated promoters
of the endogenous p53BP2 gene in HeLa cells and the RASSF1A gene in MDA-MB-231 cells are simultaneously occupied by both SETDB1 and DNMT3A proteins, which provides evidence for SETDB1
being at least partly responsible for H3-K9 trimethylation at the promoter of RASSF1A, a gene frequently silenced in human cancers. In summary, our data demonstrate the direct physical interaction and functional
connection between the H3-K9 trimethylase SETDB1 and the DNA methyltransferase DNMT3A and thus contribute to a better understanding
of the complexity of the self-reinforcing heterochromatin machinery operating at silenced promoters.

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Available from: Gerd Pfeifer, Jul 20, 2014
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    • "Interestingly, it also appears that Dnmt3a/b may take some guidance in recognising chromatin substrates through directly interacting with histone methyltransferases themselves [31]. Dnmt3a/b have been shown to interact with Suv39h1 [32] and Setdb1 [33] via their ADD domain . In the case of Setdb1, this association was essential for methylation and repression of certain CpG-methylated promoters in cancer cells. "
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    • "ERG-associated protein with SET domain (ESET), a novel histone H3K9 methyltransferase , has been shown to mediate histone methylation (Rea et al., 2000). It is also proposed that ESET may have a role in epigenetic silencing of neuronal genes through its HMTase activity (Li et al., 2006). Importantly, the ESET levels were significantly elevated in HD patients and in R6/2 transgenic mice (Ryu et al., 2006). "
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    • "DNMT3A and DNMT3B are highly expressed in early embryonic cells, the stage in which most programed de novo methylation events occur, are downregulated after differentiation and in adult somatic tissues, and are overexpressed in tumor cells (22). DNMT3B has been shown to play a crucial role in incorporating de novo hypermethylation of promoter CpG islands, a possible mechanism for tumor suppressor gene inactivation within human cancer cells (22). Another member of the DNMT3 family is DNMT3L, a regulatory factor for de novo methylation without methylation capacities (23). "
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