DNA de novo (de)Methylation in the Kidney Contributes to Salt-Induced Hypertension [RNA-seq]

Numerous adult diseases involving tissues that consist primarily of non-dividing cells are associated with changes in DNA methylation. It suggests a role for de novo methylation or demethylation of DNA, which is catalyzed by DNA methyltransferase 3 (Dnmt3) and ten-eleven translocases (Tet). However, the contribution of DNA de novo (de)methylation to these diseases remains nearly completely unproven. Broad changes in DNA methylation occurred within days in the renal outer medulla of Dahl SS rats fed a high-salt diet, a classic model of hypertension. Intra-renal administration of anti-Dnmt3a/Tet3 GapmeR’s attenuated high salt-induced hypertension in SS rats. The high salt diet induced differential expression of 1,712 genes in the renal outer medulla. Remarkably, the differential expression of 76% of these genes were prevented by anti-Dnmt3a/Tet3 GapmeR’s. The genes differentially expressed in response to the GapmeR’s were involved in the regulation of metabolism and inflammation and were significantly enriched for genes showing differential methylation in response to the GapmeR’s. These data indicate DNA de novo (de)methylation in the kidney contributes to the development of hypertension in SS rats. The findings should help to shift the paradigm of DNA methylation research in diseases involving non-dividing cells from correlative analysis to functional and mechanistic studies.诸多以主要由非分裂细胞构成的组织为病变靶点的成人疾病，均与DNA甲基化（DNA methylation）改变密切相关。这提示DNA从头甲基化（de novo methylation）或去甲基化（demethylation）发挥了关键调控作用，该过程由DNA甲基转移酶3（DNA methyltransferase 3, Dnmt3）以及Tet家族（ten-eleven translocases, Tet）催化。然而，DNA从头（去）甲基化对这类疾病的贡献度迄今几乎完全未得到证实。以高盐饮食喂养的Dahl SS大鼠（Dahl SS rats，高血压经典动物模型），其肾外髓质（renal outer medulla）可在数天内出现广泛的DNA甲基化改变。肾内给予抗Dnmt3a/Tet3 GapmeR（GapmeR），可缓解SS大鼠的高盐诱导性高血压。高盐饮食可使该大鼠肾外髓质内1712个基因出现差异表达。值得注意的是，抗Dnmt3a/Tet3 GapmeR可阻断其中76%基因的差异表达。响应GapmeR干预而发生差异表达的基因，参与代谢与炎症调控过程，且显著富集于经GapmeR干预后出现甲基化差异的基因之列。上述数据表明，肾脏内的DNA从头（去）甲基化参与了SS大鼠高血压的发生发展。本研究发现有望推动非分裂细胞相关疾病的DNA甲基化研究范式，从相关性分析转向功能与机制研究。