Genomics, Center for Molecular and Cellular Bioengineering, Biotechnology Center, Technische Universität Dresden, Dresden, Germany.
Institute for Immunology and Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
PLoS Genet. 2021 Dec 3;17(12):e1009250. doi: 10.1371/journal.pgen.1009250. eCollection 2021 Dec.
Epigenetic mechanisms are gatekeepers for the gene expression patterns that establish and maintain cellular identity in mammalian development, stem cells and adult homeostasis. Amongst many epigenetic marks, methylation of histone 3 lysine 4 (H3K4) is one of the most widely conserved and occupies a central position in gene expression. Mixed lineage leukemia 1 (MLL1/KMT2A) is the founding mammalian H3K4 methyltransferase. It was discovered as the causative mutation in early onset leukemia and subsequently found to be required for the establishment of definitive hematopoiesis and the maintenance of adult hematopoietic stem cells. Despite wide expression, the roles of MLL1 in non-hematopoietic tissues remain largely unexplored. To bypass hematopoietic lethality, we used bone marrow transplantation and conditional mutagenesis to discover that the most overt phenotype in adult Mll1-mutant mice is intestinal failure. MLL1 is expressed in intestinal stem cells (ISCs) and transit amplifying (TA) cells but not in the villus. Loss of MLL1 is accompanied by loss of ISCs and a differentiation bias towards the secretory lineage with increased numbers and enlargement of goblet cells. Expression profiling of sorted ISCs revealed that MLL1 is required to promote expression of several definitive intestinal transcription factors including Pitx1, Pitx2, Foxa1, Gata4, Zfp503 and Onecut2, as well as the H3K27me3 binder, Bahcc1. These results were recapitulated using conditional mutagenesis in intestinal organoids. The stem cell niche in the crypt includes ISCs in close association with Paneth cells. Loss of MLL1 from ISCs promoted transcriptional changes in Paneth cells involving metabolic and stress responses. Here we add ISCs to the MLL1 repertoire and observe that all known functions of MLL1 relate to the properties of somatic stem cells, thereby highlighting the suggestion that MLL1 is a master somatic stem cell regulator.
表观遗传机制是哺乳动物发育、干细胞和成年稳态中建立和维持细胞身份的基因表达模式的守门员。在许多表观遗传标记中，组蛋白 3 赖氨酸 4（H3K4）的甲基化是最广泛保守的标记之一，在基因表达中占据中心位置。混合谱系白血病 1（MLL1/KMT2A）是哺乳动物 H3K4 甲基转移酶的基础。它作为早期发病白血病的致病突变被发现，随后发现它是确定造血的建立和成年造血干细胞的维持所必需的。尽管广泛表达，但 MLL1 在非造血组织中的作用在很大程度上仍未得到探索。为了绕过造血毒性，我们使用骨髓移植和条件性突变来发现成年 Mll1 突变小鼠最明显的表型是肠道衰竭。MLL1 在肠干细胞（ISCs）和过渡扩增（TA）细胞中表达，但不在绒毛中表达。MLL1 的缺失伴随着 ISCs 的缺失和向分泌谱系的分化偏向，杯状细胞数量增加且增大。对分选的 ISCs 的表达谱分析表明，MLL1 是促进包括 Pitx1、Pitx2、Foxa1、Gata4、Zfp503 和 Onecut2 在内的几个确定的肠转录因子以及 H3K27me3 结合蛋白 Bahcc1 的表达所必需的。在肠类器官中使用条件性突变也得到了这些结果的验证。隐窝中的干细胞巢包括与 Paneth 细胞密切相关的 ISCs。ISCs 中 MLL1 的缺失促进了 Paneth 细胞中涉及代谢和应激反应的转录变化。在这里，我们将 ISCs 添加到 MLL1 谱中，并观察到 MLL1 的所有已知功能都与体细胞干细胞的特性有关，从而突出了 MLL1 是体细胞干细胞主要调控因子的这一观点。
