ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription.
ARID1A loss in adult hepatocytes activates β-catenin-mediated erythropoietin transcription.
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DOI：
10.7554/elife.53550
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发表时间：
2020-10-21
期刊：
影响因子：
7.7
通讯作者：
Colnot S
中科院分区：
文献类型：
--
作者：
Riou R;Ladli M;Gerbal-Chaloin S;Bossard P;Gougelet A;Godard C;Loesch R;Lagoutte I;Lager F;Calderaro J;Dos Santos A;Wang Z;Verdier F;Colnot S
促红细胞生成素（EPO）是红细胞生成的关键调节因子。胚胎肝脏是红细胞生成素合成的主要场所，之后肾脏接管。成人肝脏保留了表达EPO的能力，我们在这里发现了这种转录的新参与者，与经典的缺氧诱导因子途径不同。在小鼠中，在肝细胞中对染色质重塑物Arid 1a和Wnt途径的主要沉默物Apc进行遗传无效，染色质更容易接近，组蛋白标记在Epo下游增强子处变成活性标记。激活β-catenin信号增加Tcf 4/β-catenin复合物的结合并上调其增强子功能。Arid 1a和β-catenin信号的丢失导致小鼠和人类肝细胞中的细胞自主EPO转录。在单个肝细胞中Apc-Arid 1a基因无效的小鼠中，Epo从头合成导致其分泌，脾红细胞生成和急剧的红细胞增多。因此，我们确定了新的肝脏EPO调节机制刺激红细胞生成。
Erythropoietin (EPO) is a key regulator of erythropoiesis. The embryonic liver is the main site of erythropoietin synthesis, after which the kidney takes over. The adult liver retains the ability to express EPO, and we discovered here new players of this transcription, distinct from the classical hypoxia-inducible factor pathway. In mice, genetically invalidated in hepatocytes for the chromatin remodeler Arid1a, and for Apc, the major silencer of Wnt pathway, chromatin was more accessible and histone marks turned into active ones at the Epo downstream enhancer. Activating β-catenin signaling increased binding of Tcf4/β-catenin complex and upregulated its enhancer function. The loss of Arid1a together with β-catenin signaling, resulted in cell-autonomous EPO transcription in mouse and human hepatocytes. In mice with Apc-Arid1a gene invalidations in single hepatocytes, Epo de novo synthesis led to its secretion, to splenic erythropoiesis and to dramatic erythrocytosis. Thus, we identified new hepatic EPO regulation mechanism stimulating erythropoiesis.