The role of the activin cistrome in liver progenitor cell-mediated liver regeneration

激活素顺反组在肝祖细胞介导的肝再生中的作用

• 批准号: 426883873
• 负责人: Dr. Honglei Weng, Ph.D.
• 金额: --
• 依托单位: II. Medizinische Klinik: Gastroenterologie, Hepatologie, Infektiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/426883873?language=en
• 关键词: role; activin; cistrome; liver; progenitor

Activin response element (ARE) are localized in the promoters of master differentiation genes. The sequence motif is a specific binding site for the SMAD4-SMAD2/3-FOXH1 complex, involved in the regulation of embryonic stem cell (ESC) differentiation during organ development. Without extracellular signals, the entirety of ARE-directed gene expression, subsequently called the "activin cistrome", is blocked in ESC by repressive chromatin compacting factor HP1-lysine trimethylation on histone H3 complexes, thus holding ESC in a silent state. Quiescent ESC switch into differentiation mode once the activin cistrome is activated by signals from TGF- family members e.g. Nodal, activin and TGF-. Exposure of ESC to these cytokines results in the formation of complexes comprising TRIM33 and phosphorylated SMAD2 and SMAD3, which replace HP1 and uncover the ARE. Subsequently, the TGF--induced transcription factor complex SMAD4-SMAD2/3-FoxH1 binds to the activin response elements, and induces expression of master differentiation genes, initiating cell differentiation. In humans, liver progenitor cells (LPC), adult liver stem-like cells, play a crucial role in restoring liver mass and function in severe liver damage, e.g. cirrhosis, acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). Successful LPC-mediated liver regeneration requires rapid LPC differentiation into hepatocytes. It is unknown to date if LPC differentiation into hepatocytes is governed by the activin cistrome. Preliminary data for this project show that ALF or ACLF patients with a negative outcome, i.e. liver transplantation or death, showed weak or undetectable hepatic expression of p-SMAD2, TRIM33 and FOXH1. In contrast, compensated cirrhotic patients express high levels of the three transcription factors in LPC and LPC-derived hepatocytes. In vitro study further showed that LPC-to-hepatocyte differentiation required SMAD2/3, TRIM33 and FOXH1. Thus, we hypothesize that activation of the activin cistrome by chromatin remodelling is crucial for LPC differentiation into hepatocytes. This project aims to elucidate (i) whether ARE-mediated LPC differentiation occurs in patients suffering from severe liver disease, e.g. cirrhosis, ALF and ACLF; (ii) if TGF- or activin or both induce activation of the activin cistrome in LPC under these severe circumstances; (iii) how activation of the activin cistrome impacts LPC differentiation into hepatocytes in vitro and (iv) if interfering with components of the activin cistrome influences LPC-mediated liver regeneration in animals. The project will define the role and molecular mechanisms of the activin cistrome in LPC-mediated liver regeneration and enable us to harness the regenerative power of these stem-like cells in events of cirrhosis and ALF/ACLF.

激活素反应元件（AS）位于主分化基因的启动子中。序列基序是SMAD4-SMAD2/3-FOXH1复合物的特定结合位点，它参与器官发育过程中胚胎干细胞（ESC）分化的调节。没有细胞外信号，整个指导的基因表达，随后称为“激活素Cistrome”，通过反射性染色质压实因子HP1-赖氨酸三甲基化在组蛋白H3复合物上，从而阻止了ESC，从而在静音状态下保持ESC。一旦激活素Cistrome通过TGF-家族成员的信号激活，静态ESC开关进入分化模式。节点，激活素和TGF-。 ESC暴露于这些细胞因子会导致形成完成TRIM33和磷酸化的SMAD2和SMAD3的复合物，它们取代了HP1并发现了IS。随后，TGF-诱导的转录因子复合物SMAD4-SMAD2/3-FOXH1与激活素反应元件结合，并诱导掌握分化基因的表达，启动细胞分化。在人类，肝脏祖细胞（LPC），成年肝干样细胞中，在恢复肝脏质量和在严重肝脏损伤中的功能中起着至关重要的作用，例如肝硬化，急性肝衰竭（ALF）和智力肝衰竭（ACLF）。成功的LPC介导的肝脏再生需要快速的LPC分化为肝细胞。迄今为止，LPC是否分化为肝细胞是由激活素cistrome支配的，这是尚不清楚的。该项目的初步数据表明，ALF或ACLF患者的肝脏移植或死亡为阴性，显示P-SMAD2，TRIM33和FOXH1的弱或不可检测的肝表达。相比之下，补偿肝硬化患者在LPC和LPC衍生的肝细胞中表达了高水平的三个转录因子。体外研究进一步表明，LPC至羊皮细胞分化需要SMAD2/3，TRIM33和FOXH1。这就是我们假设通过染色质重塑对激活素Cistrom的激活对于LPC分化为肝细胞至关重要。该项目旨在阐明（i）患有严重肝病的患者，例如肝硬化，ALF和ACLF； （ii）如果在这种严重的情况下，如果TGF-或激活素或两者都诱导LPC中的激活素cistrome激活； （iii）激活素Cistrome的激活如何影响LPC在体外和（iv）中分化为肝细胞，如果干扰活化素Cistrome的成分会影响动物中LPC介导的肝脏再生。该项目将定义活化素cistrome在LPC介导的肝脏再生中的作用和分子机制，并使我们能够利用这些类似干细胞的再生能力在ciRRHOSIS和ALF/ACLF的事件中。