Ectopic expression of DNA methyltransferases DNMT3A2 and DNMT3L leads to aberrant hypermethylation and postnatal lethality in mice
Ectopic expression of DNA methyltransferases DNMT3A2 and DNMT3L leads to aberrant hypermethylation and postnatal lethality in mice
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DOI：
10.1002/mrd.23137
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发表时间：
2019-06-01
影响因子：
2.5
通讯作者：
Obata，Yayoi
中科院分区：
文献类型：
--
作者：
Sasaki，Keisuke;Hara，Satoshi;Obata，Yayoi
众所周知，DNA甲基化会使基因表达失活。DNA甲基转移酶（dnmt）， DNMT3A和DNMT3B，催化体细胞谱系特异性DNA甲基化，而DNMT3A和DNMT3L催化生殖细胞谱系特异性DNA甲基化。这种谱系和基因特异性DNA甲基化模式是如何产生的仍有待阐明。为了更好地理解DNA甲基化的调控机制，我们构建了组成性表达DNMT3A和DNMT3L的转基因小鼠，并分析了DNA甲基化、基因表达及其对个体发育的后续影响。所有转基因小鼠均正常出生，但在20周内死亡并伴有心脏肥厚。与野生型小鼠相比，转基因小鼠的心脏中有几种基因被抑制。这些下调基因的CpG岛在转基因小鼠中高度甲基化。这种异常甲基化发生在围产期。相反，除th19外，在所有转基因小鼠中，印迹位点上的单等位基因DNA甲基化都得到了忠实的维持。因此，DNMT3A和DNMT3L偏爱的位点在体细胞和生殖细胞谱系中是不同的。
DNA methylation is generally known to inactivate gene expression. The DNA methyltransferases (DNMTs), DNMT3A and DNMT3B, catalyze somatic cell lineage‐specific DNA methylation, while DNMT3A and DNMT3L catalyze germ cell lineage‐specific DNA methylation. How such lineage‐ and gene‐specific DNA methylation patterns are created remains to be elucidated. To better understand the regulatory mechanisms underlying DNA methylation, we generated transgenic mice that constitutively expressed DNMT3A and DNMT3L, and analyzed DNA methylation, gene expression, and their subsequent impact on ontogeny. All transgenic mice were born normally but died within 20 weeks accompanied with cardiac hypertrophy. Several genes were repressed in the hearts of transgenic mice compared with those in wild‐type mice. CpG islands of these downregulated genes were highly methylated in the transgenic mice. This abnormal methylation occurred in the perinatal stage. Conversely, monoallelic DNA methylation at imprinted loci was faithfully maintained in all transgenic mice, exceptH19. Thus, the loci preferred by DNMT3A and DNMT3L differ between somatic and germ cell lineages.