Heby O
Department of Cellular and Developmental Biology, University of Umeå, Sweden.
Int J Dev Biol. 1995 Oct;39(5):737-57.
Mammalian DNA contains relatively large amounts of a modified base, 5-methyl-cytosine (m5C). Methylation of cytosine is catalyzed by DNA(cytosine-5)methyltransferase (DNA MTase). DNA methylation seems to play an important role in the regulation of gene expression during development. Thus, m5C may inhibit transcription by preventing the binding of transcription factors and/or by altering chromatin structure. The DNA methylation patterns of the male and female pronuclei are erased in the morula and early blastula, and when the blastocyst forms, most of the DNA has become demethylated. Following implantation, however, there is a surge of de novo methylation affecting the entire genome, and already by gastrulation DNA is methylated to an extent characteristic of that of the adult animal. During subsequent development, tissue-specific genes undergo programmed demethylation, which may cause their activation. Site-directed mutagenesis of the DNA MTase gene, has recently shown that DNA methylation is absolutely required for normal development of the early mouse embryo. DNA methylation and polyamine synthesis depend on a common substrate, S-adenosylmethionine (AdoMet). As a consequence, changes in cellular polyamine levels may affect the degree of DNA methylation. When the first step in the polyamine biosynthetic pathway is blocked, F9 teratocarcinoma stem cells accumulate large amounts of decarboxylated AdoMet, the aminopropyl group donor in polyamine synthesis, and go through terminal differentiation into parietal endoderm cells. The accumulation of decarboxylated AdoMet is a direct consequence of the polyamine-depleted state of the cell. Although the decarboxylated AdoMet molecule contains a methyl group, it does not act as a methyl group donor in DNA methylation. Instead it acts as a competitive inhibitor of DNA MTase. A consequence of polyamine depletion is therefore genome-wide loss of DNA methylation due to insufficient maintenance methylation during successive rounds of DNA replication. Our recent finding that prevention of the accumulation of decarboxylated AdoMet counteracts the differentiative effect lends further support to the hypothesis proposed.
哺乳动物的DNA含有相对大量的一种修饰碱基，即5-甲基胞嘧啶（m5C）。胞嘧啶的甲基化由DNA（胞嘧啶-5）甲基转移酶（DNA MTase）催化。DNA甲基化似乎在发育过程中基因表达的调控中起重要作用。因此，m5C可能通过阻止转录因子的结合和/或改变染色质结构来抑制转录。雄原核和雌原核的DNA甲基化模式在桑椹胚和早期囊胚中被消除，当囊胚形成时，大部分DNA已去甲基化。然而，植入后，会出现影响整个基因组的从头甲基化激增，到原肠胚形成时，DNA已甲基化到成年动物特有的程度。在随后的发育过程中，组织特异性基因经历程序性去甲基化，这可能导致它们的激活。最近对DNA MTase基因进行的定点诱变表明，DNA甲基化是小鼠早期胚胎正常发育绝对必需的。DNA甲基化和多胺合成依赖于一种共同的底物，即S-腺苷甲硫氨酸（AdoMet）。因此，细胞内多胺水平的变化可能会影响DNA甲基化的程度。当多胺生物合成途径的第一步被阻断时，F9畸胎瘤干细胞会积累大量脱羧AdoMet，它是多胺合成中的氨丙基供体，并经历终末分化成为壁内胚层细胞。脱羧AdoMet的积累是细胞多胺缺乏状态的直接后果。尽管脱羧AdoMet分子含有一个甲基基团，但它在DNA甲基化中并不作为甲基供体起作用。相反，它作为DNA MTase的竞争性抑制剂起作用。因此，多胺缺乏的一个后果是由于在连续的DNA复制过程中维持甲基化不足而导致全基因组范围内的DNA甲基化缺失。我们最近的发现，即防止脱羧AdoMet的积累可抵消分化作用，进一步支持了所提出的假说。
