MLL1 is required for maintenance of intestinal stem cells
| Autor: | Dimitra Alexopoulou, Konstantinos Anastassiadis, Andreas Dahl, Julian Heuberger, Qinyu Zhang, Andrea Kranz, A. Francis Stewart, Walter Birchmeier, Neha Goveas, Kathrin Arndt, Claudia Waskow |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Gene Expression QH426-470 Biochemistry Epithelium Epigenesis Genetic Mice Animal Cells Medicine and Health Sciences Group-Specific Staining Blood and Lymphatic System Procedures Intestinal Mucosa Stem Cell Niche Organ Cultures Genetics (clinical) Bone Marrow Transplantation Staining biology Cell Staining Cell Differentiation Phenotype Cell biology Organoids Adult Stem Cells Haematopoiesis Leukemia Jejunum KMT2A Biological Cultures Anatomy Cellular Types Stem cell Myeloid-Lymphoid Leukemia Protein Research Article Adult stem cell Paneth Cells Mice Transgenic Surgical and Invasive Medical Procedures Research and Analysis Methods digestive system Intestinal Failure DNA-binding proteins Genetics medicine Animals Humans Gene Regulation Epigenetics Immunohistochemistry Techniques Molecular Biology Ecology Evolution Behavior and Systematics Transplantation Hematoxylin Staining Biology and Life Sciences Proteins Epithelial Cells Histone-Lysine N-Methyltransferase Cell Biology DNA Methylation medicine.disease Regulatory Proteins Gastrointestinal Tract Histochemistry and Cytochemistry Techniques Gene expression profiling Disease Models Animal Biological Tissue Mutagenesis Specimen Preparation and Treatment Mutation Immunologic Techniques biology.protein Digestive System Transcription Factors |
| Zdroj: | PLoS Genetics, Vol 17, Iss 12, p e1009250 (2021) PLoS Genet. 17:e1009250 (2021) PLoS Genetics |
| Popis: | 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. Author summary The ability of stem cells to replenish cellular lineages is critical for the maintenance and integrity of postnatal life. In mammals, the blood and the intestinal lining are two of the highest turnover tissues and both are anchored by stem cells. For blood, hematopoeitic stem cells require MLL1 (mixed lineage leukemia), which is an epigenetic regulator that methylates histone 3 on lysine 4 (H3K4). MLL1 was discovered because it is mutated in about 10% of all human leukemias prominently including early onset childhood leukemias. In this study we show that MLL1 is also required for maintenance of intestinal stem cells (ISCs). MLL1 is expressed in the intestinal crypt, which harbors the ISC niche and transit amplifying cells but is not expressed in the intestinal villi that line the gut. Conditional mutagenesis of Mll1 in adult mice rapidly leads to intestinal failure, wasting and death. ISCs are lost and the niche is perturbed. Loss of ISC identity can be recapitulated by conditional mutagenesis of Mll1 in intestinal organoids. In ISCs, MLL1 is required to maintain the expression of several DNA binding transcription factors that are implicated in regulating ISC cellular identity. Hence we report that two mammalian tissues with very high turnover depend upon MLL1 to maintain their respective stem cells. Together with other indications, MLL1 appears to be specifically related to adult stem cell properties. |
| Databáze: | OpenAIRE |
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