DNA 甲基化
中文名称
通路描述
胞嘧啶的甲基化由 DNA 甲基转移酶 (DNMTs) 家族催化：DNMT1、DNMT3A 和 DNMT3B 从 S-腺苷甲硫氨酸 (S-adenosylmethionine) 转移甲基基团到胞嘧啶，产生 5-甲基胞嘧啶和同型半胱氨酸 (reviewed in Klose and Bird 2006, Ooi et al. 2009, Jurkowska et al. 2011, Moore et al. 2013)。 (DNMT2 似乎甲基化 RNA 而不是 DNA。) DNMT1 是第一个被发现的酶，它优先甲基化由复制产生的半甲基化 CG 基序 (模板链甲基化，合成链未甲基化)。因此，它通过细胞分裂维持现有的甲基化。DNMT3A 和 DNMT3B 催化从头甲基化，包括 CG 二核苷酸和非 CG 基序的未甲基化位点。
成年人类 DNA 中含有约 0.76 到 1.00 摩尔百分比的 5-甲基胞嘧啶 (Ehrlich et al. 1982, reviewed in Klose and Bird 2006, Ooi et al. 2009, Moore et al. 2013)。DNA 甲基化主要发生在 CG 二核苷酸中的胞嘧啶上。CG 二核苷酸在基因组中分布不均匀。启动子区域通常具有较高的 CG 含量，形成所谓的 CG 岛 (CGIs)，而基因组其余部分的 CG 含量要低得多。CGIs 通常未甲基化，而 CGIs 以外的大多数 CG 被甲基化。启动子和第一个外显子中的甲基化倾向于抑制转录，而基因体 (启动子下游和第一个外显子之后的基因区域) 中的甲基化与转录相关 (reviewed in Ehrlich and Lacey 2013, Kulis et al. 2013)。例如 MeCP2 和 MBDs 等蛋白质特异性结合 5-甲基胞嘧啶，并可能招募其他因子。
哺乳动物的发育有两个主要的基因组-wide 去甲基化和再甲基化事件 (reviewed in Zhou 2012, Guibert and Weber 2013, Hackett and Surani 2013, Dean 2014)。在老鼠受精后约 1 天，父系基因组由 TET 蛋白、胸腺嘧啶 DNA 糖基化酶和被动稀释共同主动去甲基化，而母系基因组在复制过程中通过被动稀释去甲基化，但印记位点的甲基化被维持。受精后约 3.5 天，基因组达到最低甲基化水平。再甲基化发生在受精后约 6.5 天。第二个去甲基化和再甲基化事件发生在发育胚胎的原始生殖细胞中，受精后约 12.5 天。DNMT3A 和 DNMT3B，连同非催化性的 DNMT3L，在再甲基化事件中发挥主要作用 (reviewed in Chen and Chan 2014)。甲基转移酶如何被定向到基因组特定区域仍然是活跃的研究领域。每个位点的机制可能有所不同，但已观察到组蛋白修饰和 DNA 甲基化之间的联系 (reviewed in Rose and Klose 2014)。
成年人类 DNA 中含有约 0.76 到 1.00 摩尔百分比的 5-甲基胞嘧啶 (Ehrlich et al. 1982, reviewed in Klose and Bird 2006, Ooi et al. 2009, Moore et al. 2013)。DNA 甲基化主要发生在 CG 二核苷酸中的胞嘧啶上。CG 二核苷酸在基因组中分布不均匀。启动子区域通常具有较高的 CG 含量，形成所谓的 CG 岛 (CGIs)，而基因组其余部分的 CG 含量要低得多。CGIs 通常未甲基化，而 CGIs 以外的大多数 CG 被甲基化。启动子和第一个外显子中的甲基化倾向于抑制转录，而基因体 (启动子下游和第一个外显子之后的基因区域) 中的甲基化与转录相关 (reviewed in Ehrlich and Lacey 2013, Kulis et al. 2013)。例如 MeCP2 和 MBDs 等蛋白质特异性结合 5-甲基胞嘧啶，并可能招募其他因子。
哺乳动物的发育有两个主要的基因组-wide 去甲基化和再甲基化事件 (reviewed in Zhou 2012, Guibert and Weber 2013, Hackett and Surani 2013, Dean 2014)。在老鼠受精后约 1 天，父系基因组由 TET 蛋白、胸腺嘧啶 DNA 糖基化酶和被动稀释共同主动去甲基化，而母系基因组在复制过程中通过被动稀释去甲基化，但印记位点的甲基化被维持。受精后约 3.5 天，基因组达到最低甲基化水平。再甲基化发生在受精后约 6.5 天。第二个去甲基化和再甲基化事件发生在发育胚胎的原始生殖细胞中，受精后约 12.5 天。DNMT3A 和 DNMT3B，连同非催化性的 DNMT3L，在再甲基化事件中发挥主要作用 (reviewed in Chen and Chan 2014)。甲基转移酶如何被定向到基因组特定区域仍然是活跃的研究领域。每个位点的机制可能有所不同，但已观察到组蛋白修饰和 DNA 甲基化之间的联系 (reviewed in Rose and Klose 2014)。
英文描述
DNA methylation Methylation of cytosine is catalyzed by a family of DNA methyltransferases (DNMTs): DNMT1, DNMT3A, and DNMT3B transfer methyl groups from S-adenosylmethionine to cytosine, producing 5-methylcytosine and homocysteine (reviewed in Klose and Bird 2006, Ooi et al. 2009, Jurkowska et al. 2011, Moore et al. 2013). (DNMT2 appears to methylate RNA rather than DNA.) DNMT1, the first enzyme discovered, preferentially methylates hemimethylated CG motifs that are produced by replication (template strand methylated, synthesized strand unmethylated). Thus it maintains existing methylation through cell division. DNMT3A and DNMT3B catalyze de novo methylation at unmethylated sites that include both CG dinucleotides and non-CG motifs.
DNA from adult humans contains about 0.76 to 1.00 mole percent 5-methylcytosine (Ehrlich et al. 1982, reviewed in Klose and Bird 2006, Ooi et al. 2009, Moore et al. 2013). Methylation of DNA occurs at cytosines that are mainly located in CG dinucleotides. CG dinucleotides are unevenly distributed in the genome. Promoter regions tend to have a high CG-content, forming so-called CG-islands (CGIs), while the CG-content in the remaining part of the genome is much lower. CGIs tend to be unmethylated, while the majority of CGs outside CGIs are methylated. Methylation in promoters and first exons tends to repress transcription while methylation in gene bodies (regions of genes downstream of the promoter and first exon) correlates with transcription (reviewed in Ehrlich and Lacey 2013, Kulis et al. 2013). Proteins such as MeCP2 and MBDs specifically bind 5-methylcytosine and may recruit other factors.
Mammalian development has two major episodes of genome-wide demethylation and remethylation (reviewed in Zhou 2012, Guibert and Weber 2013, Hackett and Surani 2013, Dean 2014). In mice about 1 day after fertilization the paternal genome is actively demethylated by TET proteins together with thymine DNA glycosylase and the maternal genome is demethylated by passive dilution during replication, however methylation at imprinted sites is maintained. The genome has its lowest methylation level about 3.5 days post-fertilization. Remethylation occurs by 6.5 days post-fertilization. The second demethylation-remethylation event occurs in primordial germ cells of the developing embryo about 12.5 days post-fertilization. DNMT3A and DNMT3B, together with the non-catalytic DNMT3L, play major roles in the remethylation events (reviewed in Chen and Chan 2014). How the methyltransferases are directed to particular regions of the genome remains an area of active research. The mechanisms at each locus may differ in detail but a connection between histone modifications and DNA methylation has been observed (reviewed in Rose and Klose 2014).
DNA from adult humans contains about 0.76 to 1.00 mole percent 5-methylcytosine (Ehrlich et al. 1982, reviewed in Klose and Bird 2006, Ooi et al. 2009, Moore et al. 2013). Methylation of DNA occurs at cytosines that are mainly located in CG dinucleotides. CG dinucleotides are unevenly distributed in the genome. Promoter regions tend to have a high CG-content, forming so-called CG-islands (CGIs), while the CG-content in the remaining part of the genome is much lower. CGIs tend to be unmethylated, while the majority of CGs outside CGIs are methylated. Methylation in promoters and first exons tends to repress transcription while methylation in gene bodies (regions of genes downstream of the promoter and first exon) correlates with transcription (reviewed in Ehrlich and Lacey 2013, Kulis et al. 2013). Proteins such as MeCP2 and MBDs specifically bind 5-methylcytosine and may recruit other factors.
Mammalian development has two major episodes of genome-wide demethylation and remethylation (reviewed in Zhou 2012, Guibert and Weber 2013, Hackett and Surani 2013, Dean 2014). In mice about 1 day after fertilization the paternal genome is actively demethylated by TET proteins together with thymine DNA glycosylase and the maternal genome is demethylated by passive dilution during replication, however methylation at imprinted sites is maintained. The genome has its lowest methylation level about 3.5 days post-fertilization. Remethylation occurs by 6.5 days post-fertilization. The second demethylation-remethylation event occurs in primordial germ cells of the developing embryo about 12.5 days post-fertilization. DNMT3A and DNMT3B, together with the non-catalytic DNMT3L, play major roles in the remethylation events (reviewed in Chen and Chan 2014). How the methyltransferases are directed to particular regions of the genome remains an area of active research. The mechanisms at each locus may differ in detail but a connection between histone modifications and DNA methylation has been observed (reviewed in Rose and Klose 2014).
所含基因
33 个基因