KLF15 cistromes reveal a hepatocyte pathway governing plasma corticosteroid transport and systemic inflammation.
KLF15 cistromes reveal a hepatocyte pathway governing plasma corticosteroid transport and systemic inflammation.
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DOI：
10.1126/sciadv.abj2917
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发表时间：
2022-03-11
期刊：
影响因子：
13.6
通讯作者：
Haldar SM
中科院分区：
文献类型：
--
作者：
Jiang Z;Elsarrag SZ;Duan Q;LaGory EL;Wang Z;Alexanian M;McMahon S;Rulifson IC;Winchester S;Wang Y;Vaisse C;Brown JD;Quattrocelli M;Lin CY;Haldar SM
循环中的皮质类固醇协调应激适应，包括抑制炎症。虽然控制皮质类固醇生物合成和细胞内信号转导的途径已经很清楚，但对控制血浆皮质类固醇运输的机制知之甚少。在这里，我们发现肝细胞KLF15(Kruppel样因子15)通过直接转录激活编码皮质类固醇结合球蛋白(CBG)的Serpina6来控制血浆皮质类固醇转运和炎症反应。KLF15基因缺陷小鼠的CBG显著降低，血浆皮质类固醇结合能力降低，炎症应激期间死亡率升高。这些缺陷可以通过重组CBG完全修复，支持KLF15主要通过CBG发挥作用，控制血浆皮质酮稳态。为了了解转录机制，我们使用新设计的Klf153xFLAG小鼠产生了第一个KLF15序列。出人意料的是，肝脏KLF15主要是启动子丰富的，包括Serpina6，它结合一个回文的GC丰富的基序，打开染色质，并以最小的相关直接基因抑制反式激活基因。总体而言，我们提供了对KLF15功能的关键机制洞察，并确定了一个肝细胞固有的转录模块，它有效地调节全身皮质类固醇的运输和炎症。KLF15序列揭示的肝细胞KLF15-CBG轴控制全身皮质类固醇的转运和炎症。
Circulating corticosteroids orchestrate stress adaptation, including inhibition of inflammation. While pathways governing corticosteroid biosynthesis and intracellular signaling are well understood, less is known about mechanisms controlling plasma corticosteroid transport. Here, we show that hepatocyte KLF15 (Kruppel-like factor 15) controls plasma corticosteroid transport and inflammatory responses through direct transcriptional activation of Serpina6, which encodes corticosteroid-binding globulin (CBG). Klf15-deficient mice have profoundly low CBG, reduced plasma corticosteroid binding capacity, and heightened mortality during inflammatory stress. These defects are completely rescued by reconstituting CBG, supporting that KLF15 works primarily through CBG to control plasma corticosterone homeostasis. To understand transcriptional mechanisms, we generated the first KLF15 cistromes using newly engineered Klf153xFLAG mice. Unexpectedly, liver KLF15 is predominantly promoter enriched, including Serpina6, where it binds a palindromic GC-rich motif, opens chromatin, and transactivates genes with minimal associated direct gene repression. Overall, we provide critical mechanistic insight into KLF15 function and identify a hepatocyte-intrinsic transcriptional module that potently regulates systemic corticosteroid transport and inflammation. The hepatocyte KLF15-CBG axis, revealed by KLF15 cistromes, controls systemic corticosteroid transport and inflammation.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
3.5
作者：
Crawford AA;Bankier S;Altmaier E;Barnes CLK;Clark DW;Ermel R;Friedrich N;van der Harst P;Joshi PK;Karhunen V;Lahti J;Mahajan A;Mangino M;Nethander M;Neumann A;Pietzner M;Sukhavasi K;Wang CA;Bakker SJL;Bjorkegren JLM;Campbell H;Eriksson J;Gieger C;Hayward C;Jarvelin MR;McLachlan S;Morris AP;Ohlsson C;Pennell CE;Price J;Rudan I;Ruusalepp A;Spector T;Tiemeier H;Völzke H;Wilson JF;Michoel T;Timpson NJ;Smith GD;Walker BR;CORtisol NETwork (CORNET) consortium
通讯作者：
CORtisol NETwork (CORNET) consortium
影响因子：
56.9
作者：
Gifford, Casey A.;Ranade, Sanjeev S.;Srivastava, Deepak
通讯作者：
Srivastava, Deepak
影响因子：
4.8
作者：
BARTALENA, L;HAMMOND, GL;ROBBINS, J
通讯作者：
ROBBINS, J
影响因子：
14.9
作者：
Haeussler M;Zweig AS;Tyner C;Speir ML;Rosenbloom KR;Raney BJ;Lee CM;Lee BT;Hinrichs AS;Gonzalez JN;Gibson D;Diekhans M;Clawson H;Casper J;Barber GP;Haussler D;Kuhn RM;Kent WJ
通讯作者：
Kent WJ