Natural variation in DNA methylation homeostasis and the emergence of epialleles
Natural variation in DNA methylation homeostasis and the emergence of epialleles
复制标题
DOI：
10.1073/pnas.1918172117
复制
发表时间：
2020-02
期刊：
影响因子：
--
通讯作者：
Yinwen Zhang;Jered M. Wendte;Lexiang Ji;Robert J. Schmitz
中科院分区：
文献类型：
--
作者：
Yinwen Zhang;Jered M. Wendte;Lexiang Ji;Robert J. Schmitz
DNA甲基化是一种重要的染色质修饰，有助于描述异染色质和转录沉默。破坏DNA甲基化对异染色质的强大靶向的突变导致可以改变转录的基因上的异位DNA甲基化。通过研究数百种模式植物拟南芥（Arabidopsis thaliana）的DNA甲基化变异，我们发现证据表明，DNA甲基化对异染色质的靶向性是该物种的一个特征。异染色质甲基化水平较低的植物基因型具有更多的DNA甲基化基因，这些基因容易发生转录沉默。这些结果表明，表观遗传等位基因可以作为维持异染色质相关DNA甲基化的副产品而产生。在植物和哺乳动物中，DNA甲基化通过将异染色质与转录活性的常染色质区分开来，在转录沉默中起着关键作用。异染色质和常染色质之间的稳态平衡对基因组的稳定至关重要。这在许多异染色质维持的疾病和突变体中都很明显，其特征是DNA甲基化的整体损失加上改变转录的DNA甲基化的局部异位增益。此外，我们已经表明，拟南芥的全基因组甲基化模式在几代之间是高度稳定的，除了罕见的外胚轴。然而，在靶向DNA甲基化到异染色质的稳健性中存在的自然变异程度，以及这种变异的表型后果，仍有待充分探索。本研究发现，在725份拟南芥材料中，异染色质和基因DNA甲基化具有高度的差异性。我们发现基因DNA甲基化与异染色质中的甲基化呈负相关，这表明某些甲基化途径可能在异染色质缺失时被重定向到基因上。这种再分配可能涉及到一个涉及DNA甲基转移酶、染色质甲基化酶3 （CMT3）、H3K9me2和组蛋白转换的反馈回路，因为高表达、具有高密度CMT3首选CWG位点的长基因更容易被甲基化。重要的是，虽然基因中单独存在CG甲基化可能不会影响转录，但含有CG甲基化的基因更有可能在非CG位点被甲基化并沉默。这些发现与DNA甲基化稳态的自然变化可能是改变表型的外显子进化的基础的假设是一致的。
Significance DNA methylation is an important chromatin modification that helps delineate heterochromatin and transcriptional silencing. Mutations that disrupt robust targeting of DNA methylation to heterochromatin result in ectopic DNA methylation on genes that can alter transcription. By examining variation in DNA methylation among hundreds of natural accessions of the model plant Arabidopsis thaliana, we found evidence that robust targeting of DNA methylation to heterochromatin is a trait that varies within this species. Plant genotypes that had lower levels of methylation in heterochromatin had more genes with DNA methylation, and these genes were prone to transcriptional silencing. These results reveal that epigenetic alleles can arise as a byproduct of maintaining methylation of heterochromatin-associated DNA. In plants and mammals, DNA methylation plays a critical role in transcriptional silencing by delineating heterochromatin from transcriptionally active euchromatin. A homeostatic balance between heterochromatin and euchromatin is essential to genomic stability. This is evident in many diseases and mutants for heterochromatin maintenance, which are characterized by global losses of DNA methylation coupled with localized ectopic gains of DNA methylation that alter transcription. Furthermore, we have shown that genome-wide methylation patterns in Arabidopsis thaliana are highly stable over generations, with the exception of rare epialleles. However, the extent to which natural variation in the robustness of targeting DNA methylation to heterochromatin exists, and the phenotypic consequences of such variation, remain to be fully explored. Here we describe the finding that heterochromatin and genic DNA methylation are highly variable among 725 A. thaliana accessions. We found that genic DNA methylation is inversely correlated with that in heterochromatin, suggesting that certain methylation pathway(s) may be redirected to genes upon the loss of heterochromatin. This redistribution likely involves a feedback loop involving the DNA methyltransferase, CHROMOMETHYLASE 3 (CMT3), H3K9me2, and histone turnover, as highly expressed, long genes with a high density of CMT3-preferred CWG sites are more likely to be methylated. Importantly, although the presence of CG methylation in genes alone may not affect transcription, genes containing CG methylation are more likely to become methylated at non-CG sites and silenced. These findings are consistent with the hypothesis that natural variation in DNA methylation homeostasis may underlie the evolution of epialleles that alter phenotypes.