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-蛋氨酸作为甲基供体。蛋氨酸腺苷转移酶(MAT)利用蛋氨酸和三磷酸腺苷两种底物生物合成SAM。在哺乳动物中已经鉴定出三种不同形式的MAT(MATI、MATII和MATIII)，它们由两个不同的基因(MAT1A和MAT2A)编码。MATII由MATA编码的α-2催化亚基和MAT2B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阻遏子，形成SAM整合转录调控模块(SAMIT)，影响组蛋白甲基转移酶的活性。然而，由MATIIα和β或与其相关的甲基转移酶调控的基因的身份尚不清楚。我和我的合作者发现，MATII通过与组蛋白H3K9甲基转移酶SETDB1特异性地相互作用，抑制由PTGS2编码的环氧合酶2(COX-2)的表达，从而促进COX-2基因上H3K9的三甲基化。我们讨论了MATII的基因特异性功能和表观基因组功能。

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.