Notes on the role of dynamic DNA methylation in mammalian development
Notes on the role of dynamic DNA methylation in mammalian development
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DOI：
10.1073/pnas.1415301111
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发表时间：
2015-06-02
影响因子：
11.1
通讯作者：
Boulard, Mathieu
中科院分区：
文献类型：
--
作者：
Bestor, Timothy H.;Edwards, John R.;Boulard, Mathieu
自从有人提出基因组甲基化模式可能在S期通过维持性甲基化进行传递，并可能在发育过程中对基因表达的动态调控起作用以来，已经过去了将近40年[霍利迪R，普格JE（1975年）《科学》187(4173): 226 - 232；里格斯AD（1975年）《细胞遗传学与细胞遗传学》14(1): 9 - 25]。这一革命性的提议是基于当时普遍存在的“我们对发育过程中遗传程序展开的机制几乎完全无知”这一情况而提出的。从那以后，有许多关于转录激活和去甲基化之间相关性的报道，但因果关系尚未得到证实，而且到目前为止，没有合理的证据证明存在一个通过可逆的DNA甲基化来激活和抑制基因的复杂生化系统。这样一个系统将补充或取代在具有未甲基化基因组（如秀丽隐杆线虫和双翅目昆虫）以及那些对其基因组进行甲基化的生物中调节细胞分化的保守的转录因子网络。DNA甲基化在不可逆的启动子沉默中确实起着重要作用，比如在印记基因的单等位基因表达、转座子的沉默以及雌性哺乳动物的X染色体失活中。DNA甲基化并没有强化或取代在具有甲基化或未甲基化基因组的生物之间保守的调控途径，而是赋予基因组一种能力，即使在存在表达所需的所有因子的情况下，也能使特定序列发生不可逆的转录沉默，而这种能力对于具有未甲基化基因组的生物来说通常是不存在的。
It has been nearly 40 y since it was suggested that genomic methylation patterns could be transmitted via maintenance methylation during S phase and might play a role in the dynamic regulation of gene expression during development [Holliday R, Pugh JE (1975) Science 187(4173): 226-232; Riggs AD (1975) Cytogenet Cell Genet 14(1): 9-25]. This revolutionary proposal was justified by "... our almost complete ignorance of the mechanism for the unfolding of the genetic program during development" that prevailed at the time. Many correlations between transcriptional activation and demethylation have since been reported, but causation has not been demonstrated and to date there is no reasonable proof of the existence of a complex biochemical system that activates and represses genes via reversible DNA methylation. Such a system would supplement or replace the conserved web of transcription factors that regulate cellular differentiation in organisms that have unmethylated genomes (such as Caenorhaditis elegans and the Dipteran insects) and those that methylate their genomes. DNA methylation does have essential roles in irreversible promoter silencing, as in the monoallelic expression of imprinted genes, in the silencing of transposons, and in X chromosome inactivation in female mammals. Rather than reinforcing or replacing regulatory pathways that are conserved between organisms that have either methylated or unmethylated genomes, DNA methylation endows genomes with the ability to subject specific sequences to irreversible transcriptional silencing even in the presence of all of the factors required for their expression, an ability that is generally unavailable to organisms that have unmethylated genomes.