Dot1l deficiency leads to increased intercalated cells and upregulation of V-ATPase B1 in mice.
Dot1l deficiency leads to increased intercalated cells and upregulation of V-ATPase B1 in mice.
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DOI：
10.1016/j.yexcr.2015.09.014
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发表时间：
2016-06-10
影响因子：
3.7
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Xiao Z;Chen L;Zhou Q;Zhang W
哺乳动物肾脏的集尿管由主细胞（PCs）和插层细胞（ic）组成，它们分别调节电解质/液体和酸碱平衡。PC和IC分化的表观遗传调控因子尚不清楚。我们之前分别使用Aqp2和V-ATPase B1B2来标记pc和ic。我们发现，在表达aqp2的细胞（Dot1lAC）中，组蛋白H3 K79甲基转移酶Dot1l被破坏的小鼠比Dot1lf/f具有约20%的ic，并伴有相似的PCs减少。在这里，我们使用各种PC和IC标记物进行了多次双免疫荧光染色，并证实了这一发现。α-IC和β-IC群体在Dot1lAC和Dot1lf/f中均显著扩增。这些变化与V-ATPase B1和B2的显著上调有关，但与Aqp2、AE1和Pendrin无关。染色质免疫沉淀分析显示，在Atp6v1b1 5 '侧区结合的Dot1l和H3K79二甲基化显著减少。在IMCD3细胞中，Dot1a的过表达显著下调了由Atp6v1b1启动子驱动的稳定转染的荧光素酶报告基因。当甲基转移酶死亡突变体过表达时，这种下调受到损害，但并未完全消除。综上所述，我们的数据表明Dot1l是PC和IC分化的一个新的表观遗传调控因子，而Atp6v1b1是Dot1l的一个新的转录靶点。
The collecting duct in the mammalian kidney consists of principal cells (PCs) and intercalated cells (ICs), which regulate electrolyte/fluid and acid/base balance, respectively. The epigenetic regulators of PC and IC differentiation remain obscure. We previously used Aqp2 and V-ATPase B1B2 to label PCs and ICs, respectively. We found that mice with histone H3 K79 methyltransferase Dot1l disrupted in Aqp2-expressing cells (Dot1lAC) vs. Dot1lf/f possessed ~20% more ICs coupled with a similar decrease in PCs. Here, we performed multiple double immunofluorescence staining using various PC and IC markers and confirmed that this finding. Both α-IC and β-IC populations were significantly expanded in Dot1lAC vs. Dot1lf/f. These changes are associated with significantly upregulated V-ATPase B1 and B2, but not Aqp2, AE1, and Pendrin. Chromatin immunoprecipitation assay unveiled a significant reduction of Dot1l and H3K79 di-methylation bound at the Atp6v1b1 5′ flanking region. Overexpression of Dot1a significantly downregulated a stably-transfected luciferase reporter driven by the Atp6v1b1 promoter in IMCD3 cells. This downregulation was impaired, but not completely abolished when a methyltransferase-dead mutant was overexpressed. Taken together, our data suggest that Dot1l is a new epigenetic regulator of PC and IC differentiation and Atp6v1b1 is a new transcriptional target of Dot1l.
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影响因子：
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作者：
Chen L;Zhang X;Zhang W
通讯作者：
Zhang W
DOI：
10.1152/ajprenal.00105.2010
发表时间：
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