mAM Facilitates Conversion by ESET of Dimethyl to Trimethyl Lysine 9 of Histone H3 to Cause Transcriptional Repression

Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Molecular Cell (Impact Factor: 14.02). 09/2003; 12(2):475-87. DOI: 10.1016/j.molcel.2003.08.007
Source: PubMed


Methylation of histone tails plays an important role in chromatin structure and function. Previously, we reported that ESET/SETDB1 is a histone methyltransferase (HMTase). Here, we show that SETDB1 tightly associates with the human homolog of mAM, a murine ATFa-associated factor. Although recombinant ESET can methylate lysine 9 of histone H3 (H3-K9), its activity is severely compromised when compared to that of the ESET/mAM complex. mAM stimulates ESET enzymatic activity by increasing the Vmax and decreasing the Km. Importantly, mAM facilitates the ESET-dependent conversion of dimethyl H3-K9 to the trimethyl state both in vitro and in vivo. Chromatin-based transcription and ChIP analyses demonstrate that mAM enhances ESET-mediated transcriptional repression in a SAM-dependent manner, and this repression correlates with H3-K9 trimethylation at the promoter. Thus, our studies establish that promoter H3-K9 trimethylation is the cause of transcriptional repression and that mAM/hAM facilitates conversion of H3-K9 dimethyl to trimethyl by ESET/SETDB1.

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Available from: Hediye Erdjument-Bromage, May 05, 2015
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    • "SET domain, bifurcated 1 (SETDB1) is a histone methyltransferase (HMT) that methylates lysine 9 on histone H3 (H3K9) [12]. The enzymatic activity of SETDB1, in association with MBD1- containing chromatin-associated factor 1 (MCAF1), converts H3K9me2 to H3K9me3 and represses subsequent transcription [8] [13]. SETDB1 is amplified in cancers such as melanoma and lung cancer, and increased expression of SETDB1 promotes tumorigenesis in a zebrafish melanoma model [14] [15]. "
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    • "Methylation of H3 on lysine 9 (H3K9me) is associated with gene silencing and mediated by histone lysine methyltransferases (HKMT) including SETDB1 [14] [15] [16] [17]. "
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    • "Methylation at these sites leads to gene silencing through the binding of histone methyl domain binding proteins (Adams-Cioaba & Min, 2009). G9a and GLP are the main enzymes responsible for catalyzing H3K9me2 modifications (Shinkai & Tachibana, 2011; Tachibana et al., 2005), and SETDB1 can catalyze the formation of both H3K9me2 and H3K9me3 (Wang et al., 2003; Zee et al., 2010). "
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