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Dnmt3a and Dnmt3b-Decommissioned Fetal Enhancers are Linked to Kidney Disease.
Journal of the American Society of Nephrology ( IF 10.3 ) Pub Date : 2020-03-03 , DOI: 10.1681/asn.2019080797
Yuting Guan 1 , Hongbo Liu 1 , Ziyuan Ma 2 , Szu-Yuan Li 2 , Jihwan Park 1 , Xin Sheng 1 , Katalin Susztak 2
Affiliation  

BACKGROUND Cytosine methylation is an epigenetic mark that dictates cell fate and response to stimuli. The timing and establishment of methylation logic during kidney development remains unknown. DNA methyltransferase 3a and 3b are the enzymes capable of establishing de novo methylation. METHODS We generated mice with genetic deletion of Dnmt3a and Dnmt3b in nephron progenitor cells (Six2 Cre Dnmt3a/3b) and kidney tubule cells (Ksp Cre Dnmt3a/3b). We characterized Ksp Cre Dnmt3a/3b mice at baseline and after injury. Unbiased omics profiling, such as whole genome bisulfite sequencing, reduced representation bisulfite sequencing and RNA sequencing were performed on whole-kidney samples and isolated renal tubule cells. RESULTS Ksp Cre Dnmt3a/3b mice showed no obvious morphologic and functional alterations at baseline. Knockout animals exhibited increased resistance to cisplatin-induced kidney injury, but not to folic acid-induced fibrosis. Whole-genome bisulfite sequencing indicated that Dnmt3a and Dnmt3b play an important role in methylation of gene regulatory regions that act as fetal-specific enhancers in the developing kidney but are decommissioned in the mature kidney. Loss of Dnmt3a and Dnmt3b resulted in failure to silence developmental genes. We also found that fetal-enhancer regions methylated by Dnmt3a and Dnmt3b were enriched for kidney disease genetic risk loci. Methylation patterns of kidneys from patients with CKD showed defects similar to those in mice with Dnmt3a and Dnmt3b deletion. CONCLUSIONS Our results indicate a potential locus-specific convergence of genetic, epigenetic, and developmental elements in kidney disease development.

中文翻译:


Dnmt3a 和 Dnmt3b 停用的胎儿增强剂与肾脏疾病有关。



背景技术胞嘧啶甲基化是决定细胞命运和对刺激的反应的表观遗传标记。肾脏发育过程中甲基化逻辑的时间和建立仍然未知。 DNA 甲基转移酶 3a 和 3b 是能够建立从头甲基化的酶。方法 我们生成了肾单位祖细胞 (Six2 Cre Dnmt3a/3b) 和肾小管细胞 (Ksp Cre Dnmt3a/3b) 中 Dnmt3a 和 Dnmt3b 基因缺失的小鼠。我们对 Ksp Cre Dnmt3a/3b 小鼠的基线和损伤后进行了表征。对全肾样本和分离的肾小管细胞进行了无偏见的组学分析,例如全基因组亚硫酸氢盐测序、简化代表性亚硫酸氢盐测序和RNA测序。结果 Ksp Cre Dnmt3a/3b 小鼠在基线时没有表现出明显的形态和功能改变。基因敲除动物对顺铂引起的肾损伤表现出增强的抵抗力,但对叶酸引起的纤维化没有增强的抵抗力。全基因组亚硫酸氢盐测序表明,Dnmt3a 和 Dnmt3b 在基因调控区甲基化中发挥重要作用,这些基因调控区在发育中的肾脏中充当胎儿特异性增强子,但在成熟的肾脏中不再发挥作用。 Dnmt3a 和 Dnmt3b 的缺失导致发育基因沉默失败。我们还发现 Dnmt3a 和 Dnmt3b 甲基化的胎儿增强子区域富含肾脏疾病遗传风险位点。 CKD 患者肾脏的甲基化模式显示出与 Dnmt3a 和 Dnmt3b 缺失小鼠相似的缺陷。结论 我们的结果表明肾脏疾病发展中遗传、表观遗传和发育因素可能存在位点特异性趋同。
更新日期:2020-04-01
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