Epigenetic connection.ppt

* * * * * In the northern blot assay Alcohol dehydrogennase-1 (Adh-1) and GlutathionS-transferase Yc2 (GST-Yc2)] wereupregulated and l-serine dehydratase (Lsdh) and Cytochrome P450 2C11 (CYP2C11) were down regulated by ethanol. CHIP assay demonstrating association of histone H3me2K9 and H3me2K4 methylation at the promoter of the genes up- and downregulated by ethanol in hepatocytes. Treatment of hepatocytes with ethanol reduces H3 Lysine-9 methylation with subsequent increase of H3 Lysine-4 methylation in the regulatory region of the upregulatory genes. Whereas, in down regulatory genes, the dimethyl Lysine-9 accumulated at the promoter with negligible trace of Lysine-4 methylated histone H3 * * * Methylation occurs on the side-chain N of Lysine and Arginine by HMT (histone methyltransferases) HMTs transfer the methyl group from SAM, which is universal methyl donor for methyltransferases, to the lysine or arginine residues on histones Arginine can be either mono- or di-methylated and lysine can be mono-, di-, trimethylated. While DNA is only mono-methylated on cytosine base. This is distinct difference between DNA methylation and histone methylation. Methylation can result in either transcriptional activation or repression, depending on the residues and the pattern of other modifications. By contrast, LSD1 is highly selective for H3-K4 mono-and di-methylation but cannot demethylate H3-K4 tri-methylation * * These are some of examples which show histone lysine methylation plays an important role in tumor suppressor gene silencing. These two studies have been done in colon cancer cells. In colon cancer cell lines, deacetylation and methylation at H3-K9 were related with promoter DNA methylation-associated MLH1 promoter. Kondo’s study in three different colon cancer cell lines, reduced H3-K4 methylation and increased H3-K9 play a critical role to maintain promoter methylation-associated silencing of p16, MLH1, MGMT. * * * FIG. 1. ? Two-step model of SWI/