Epigenome regulation for coupling of SAM synthesis and histone methylation

组蛋白和DNA甲基转移酶利用含硫氨基酸代谢的关键中间体S-腺苷-L-甲硫氨酸（SAM，或SAMet）作为甲基的供体。SAM由甲硫氨酸腺苷转移酶（MAT）使用两种底物甲硫氨酸和ATP生物合成。已经在哺乳动物中鉴定了由两种不同基因（MAT 1A和MAT 2A）编码的三种不同形式的MAT（MATI、MATII和MATIII）。MATII由MAT 2A编码的α2催化亚基和MAT 2B编码的β调节亚基组成，但β亚基的生理功能尚不清楚。MATII在氧化应激反应中作为转录辅抑制因子，形成SAM整合转录调控模块（SAMIT），影响组蛋白甲基转移酶活性。然而，由MATIIα和β或其相关甲基转移酶调控的基因的身份尚不清楚。我的合作者和我表明，MATII抑制环加氧酶2（考克斯-2）的表达编码的Ptgs 2，通过特异性地与组蛋白H3 K9甲基转移酶SETDB 1相互作用，从而促进三甲基化的H3 K9在考克斯-2基因座。我们讨论了MATII的基因特异性和表观基因组范围内的功能。

Histone and DNA methyltransferases utilized S-adenosyl-L-methioine (SAM, or AdoMet), a key intermediate of sulfur amino acid metabolism, as a donor of methyl group. SAM is biosynthesized by methionine adenosyltransferase (MAT) using two substrates, methionine and ATP. Three distinct forms of MAT (MATI, MATII and MATIII), encoded by two distinct genes (MAT1A and MAT2A), have been identified in mammals. MATII consists of α2 catalytic subunit encoded by MAT2A and β regulatory subunit encoded by MAT2B, but the physiological function of the β subunit is till unknown. MATII serves as a transcriptional corepressor in the oxidative stress response and forms the SAM-integrating transcription regulation module (SAMIT), affecting histone methyltransferase activities. However, the identities of genes regulated by MATIIα and β or its associated methyltransferases are unclear. My collaborators and I show that MATII represses the expression of cyclooxygenase 2 (COX-2) encoded by Ptgs2, by specifically interacting with histone H3K9 methyltransferase SETDB1, thereby promoting the trimethylation of H3K9 at the COX-2 locus. We discuss both gene-specific and epigenome-wide functions of MATII.