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The relationship between Mll1 and Notch signaling in epithelial stem cell homeostasis

Mll1和Notch信号在上皮干细胞稳态中的关系

基本信息

批准号：
202210441
负责人：
Professor Dr. Adrian Francis Stewart
金额：
--
依托单位：
Biotechnologisches Zentrum (Biotec)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2011
资助国家：
德国
起止时间：
2010-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/202210441?language=en
关键词：
relationship between Mll1 Notch signaling

项目摘要

Mixed lineage leukemia (Mll1) is the founding member of the mammalian family of six H3K4 methyltransferases. It was discovered as the main gene mutated in early onset leukemia and subsequently found to be required for the establishment and maintenance of hematopoietic stem cells. However, although ubiquitously expressed, the roles of Mll1 in non-hematopoietic tissues remain largely unexplored. In our previous DFG project, we found that loss of Mll1 in adult mice results in rapid failure of small intestinal function. Remarkably, the observed intestinal defect - an expansion of secretory cells together with a depletion of the stem cell compartment - recapitulated Notch signaling blockage in intestinal crypt stem cells. Consequently, we aim to decipher the role of Mll1 in the intestinal system and its relationship to Notch signaling. We propose that either Mll1 is required for expression of a component(s) of the Notch signaling pathway or is physically required at Notch target genes for Notch transcriptional responses. Using conditional mutagenesis in mice and organoids, we will identify Mll1 target genes by transcriptome profiling and chromatin immunoprecipitation studies. We will also investigate the embryonic role of Mll1 in the establishment of intestinal stem cells and determine whether Mll1 can re-establish functional crypts in adults upon re-expression after removal. In addition to tamoxifen-induced Cre/loxP conditional mutagenesis, we will explore the application of a new ligand-inducible loss-of-function strategy in mice based on the auxin-inducible degron. Our primary discovery connecting Mll1 to Notch signaling in intestinal stem cells has implications for other epithelial stem cell compartments where Notch signaling is also implicated. The link between Mll1 and Notch signaling in different epithelial compartments could be fundamental to all epithelial stem cells and central to mechanisms of epithelial tumorigenesis.

混合血统白血病(Mll1)是哺乳动物六种H3K4甲基转移酶家族的创始成员。它被发现是早发性白血病的主要基因突变，随后被发现是建立和维持造血干细胞所必需的。然而，尽管MLL1在非造血组织中普遍表达，但其作用在很大程度上仍未被研究。在我们之前的DFG项目中，我们发现成年小鼠MLL1的缺失会导致迅速的小肠功能衰竭。值得注意的是，观察到的肠道缺陷--分泌细胞的扩张和干细胞隔室的耗尽--概括了肠隐窝干细胞中Notch信号的阻断。因此，我们的目标是破译MLL1在肠道系统中的作用及其与Notch信号的关系。我们认为，M111是Notch信号通路的一个组成部分(S)表达所必需的，或者是Notch转录反应的靶基因所必需的。利用在小鼠和有机化合物中的条件突变，我们将通过转录组图谱和染色质免疫沉淀研究来确定MLL1靶基因。我们还将研究MLL1在建立肠道干细胞中的胚胎作用，并确定MLL1在移除后重新表达后能否在成人体内重建有功能的隐窝。除了他莫昔芬诱导的Cre/loxP条件突变外，我们还将探索一种新的基于生长素诱导的降解的配体诱导的功能丧失策略在小鼠中的应用。我们的初步发现将肠干细胞中的M111信号与Notch信号联系起来，这对Notch信号也涉及到的其他上皮干细胞亚群也有意义。MLL1和Notch信号在不同的上皮室之间的联系可能是所有上皮性干细胞的基础，也是上皮性肿瘤发生机制的核心。