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Goveas, N.* ; Waskow, C.* ; Arndt, K.* ; Heuberger, J.* ; Zhang, Q.* ; Alexopoulou, D. ; Dahl, A.* ; Birchmeier, W.* ; Anastassiadis, K.* ; Stewart, A.F.* ; Kranz, A.*

MLL1 is required for maintenance of intestinal stem cells.

PLoS Genet. 17:e1009250 (2021)
Postprint Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Histone Methyltransferase; Transcription Factors; Synaptic Plasticity; H3k4 Trimethylation; Salivary-gland; Gene; Expression; Crypt; Methylation; Recombination
Sprache englisch
Veröffentlichungsjahr 2021
HGF-Berichtsjahr 2021
ISSN (print) / ISBN 1553-7390
e-ISSN 1553-7404
Zeitschrift PLoS Genetics
Quellenangaben Band: 17, Heft: 12, Seiten: , Artikelnummer: e1009250 Supplement: ,
Verlag Public Library of Science (PLoS)
Verlagsort 1160 Battery Street, Ste 100, San Francisco, Ca 94111 Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pancreatic Islet Research (IPI)
POF Topic(s) 90000 - German Center for Diabetes Research
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-502600-001
Förderungen central resources of the MDC
SAW program on collaborative excellence of the Leibniz Association
DFG
Deutsche Forschungsgemeinschaft (DFG)
DOI 10.1371/journal.pgen.1009250
WOS ID WOS:000726546100001
Scopus ID 85121899469
PubMed ID 34860830
Erfassungsdatum 2022-02-01
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