Regulation of αENaC transcription.
Regulation of αENaC transcription.
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DOI：
10.1016/bs.vh.2014.12.004
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发表时间：
2015
影响因子：
--
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Chen L;Zhang X;Zhang W
醛固酮是Na+吸收的主要调节剂，并且主要通过在多个水平上控制上皮Na+通道（ENaC）功能（包括转录）起作用。ENaC由α、β和γ亚基组成。在经典模型中，醛固酮主要通过激活盐皮质激素受体（MR）来增强转录。然而，醛固酮如何诱导染色质改变，从而导致基因激活或抑制仍然在很大程度上未知。新的证据表明Dot 1a-Af 9复合物通过直接结合和调节αENaC启动子特定亚区的靶向组蛋白H3 K79超甲基化在抑制αENaC中起重要作用。醛固酮通过降低Dot 1a和Af 9的表达并通过诱导Sgk 1来损害Dot 1a-Af 9的形成，Sgk 1反过来使Af 9在S435处磷酸化以减弱Dot 1a-Af 9相互作用。MR通过与Dot 1a竞争结合Af 9来平衡Dot 1a-Af 9作用。Af 17通过与Dot 1a竞争性相互作用并促进Dot 1a核输出来解抑制αENaC。因此，MR−/−小鼠在出生后第5天ENaC表达受损，这可能有助于后期假性醛固酮减少症1型的进展。Af 17 −/−小鼠的ENaC表达、肾脏Na+潴留和血压降低。相比之下，Dot 1 lAC小鼠的αENaC表达增加，尽管主细胞减少了20%。本章回顾了这些发现连接醛固酮行动ENaC转录通过染色质修饰。未来的方向，对理解的作用Dot 1a-Af 9复杂ENaC调控以外，特别是在肾纤维化也简要讨论。
Aldosterone is a major regulator of Na+ absorption and acts primarily by controlling the epithelial Na+ channel (ENaC) function at multiple levels including transcription. ENaC consists of α, β, and γ subunits. In the classical model, aldosterone enhances transcription primarily by activating mineralocorticoid receptor (MR). However, how aldosterone induces chromatin alternation and thus leads to gene activation or repression remains largely unknown. Emerging evidence suggests that Dot1a-Af9 complex plays an important role in repression of αENaC by directly binding and modulating targeted histone H3 K79 hypermethylation at the specific subregions of αENaC promoter. Aldosterone impairs Dot1a–Af9 formation by decreasing expression of Dot1a and Af9 and by inducing Sgk1, which, in turn, phosphorylates Af9 at S435 to weaken Dot1a–Af9 interaction. MR counterbalances Dot1a–Af9 action by competing with Dot1a for binding Af9. Af17 derepresses αENaC by competitively interacting with Dot1a and facilitating Dot1a nuclear export. Consistently, MR−/− mice have impaired ENaC expression at day 5 after birth, which may contribute to progressive development of pseudohypoaldosteronism type 1 in a later stage. Af17−/− mice have decreased ENaC expression, renal Na+ retention, and blood pressure. In contrast, Dot1lAC mice have increased αENaC expression, despite a 20% reduction of the principal cells. This chapter reviews these findings linking aldosterone action to ENaC transcription through chromatin modification. Future direction toward the understanding the role of Dot1a–Af9 complex beyond ENaC regulation, in particular, in renal fibrosis is also briefly discussed.