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MLL1 is required for maintenance of intestinal stem cells and the expression of the cell adhesion molecule JAML

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Title:MLL1 is required for maintenance of intestinal stem cells and the expression of the cell adhesion molecule JAML
Creators Name:Goveas, N. and Waskow, C. and Arndt, K. and Heuberger, J. and Zhang, Q. and Alexopoulou, D. and Dahl, A. and Birchmeier, W. and Anastassiadis, K. and Stewart, A.F. and Kranz, A.
Abstract:Epigenetic control is crucial for lineage-specific gene expression that creates cellular identity during mammalian development and in adult organism. Histone 3 lysine 4 methylation (H3K4) is a universal epigenetic mark. Mixed lineage leukemia (MLL1) is the founding member of the mammalian family of H3K4 methyltransferases. It was originally discovered as the main gene mutated in early onset leukemias and then found to be required for hematopoietic stem cell development and maintenance. However, 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 Mll1-mutant mice is intestinal failure. Loss of MLL1 is accompanied by a differentiation bias towards the secretory lineage with increased numbers of goblet cells. MLL1 is expressed in intestinal stem cells (ISCs) and transit amplifying (TA) cells but at reduced levels in Paneth cells and not in the villus. MLL1 is required for the maintenance of intestinal stem cells (ISCs) and proliferation in the crypt. Transcriptome analysis implicate MLL1-dependent expression in ISCs of several transcription factors including Pitx2, Gata4, Foxa1 and Onecut2, and also a cell adhesion molecule, Jaml. Reactive transcriptome changes in Paneth cells and organoids imply that JAML plays a key role in the crypt stem cell niche. All known postnatal functions of MLL1 relate to stem cell maintenance and lineage decisions thereby highlighting the suggestion that MLL1 is a master stem cell regulator.
Keywords:Animals, Mice
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2020.11.19.389528
Date:19 November 2020
Official Publication:https://doi.org/10.1101/2020.11.19.389528
Related to:
https://edoc.mdc-berlin.de/21144/Final version

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