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
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