MLL1 is required for maintenance of intestinal stem cells.
Adult Stem Cells
/ physiology
Animals
Bone Marrow Transplantation
Cell Differentiation
/ genetics
DNA Methylation
Disease Models, Animal
Epigenesis, Genetic
Histone-Lysine N-Methyltransferase
/ genetics
Humans
Intestinal Failure
/ genetics
Intestinal Mucosa
/ cytology
Jejunum
/ cytology
Mice
Mice, Transgenic
Mutagenesis
Mutation
Myeloid-Lymphoid Leukemia Protein
/ genetics
Stem Cell Niche
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
09
10
2020
accepted:
30
10
2021
entrez:
3
12
2021
pubmed:
4
12
2021
medline:
24
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34860830
doi: 10.1371/journal.pgen.1009250
pii: PGENETICS-D-20-01516
pmc: PMC8641872
doi:
Substances chimiques
Myeloid-Lymphoid Leukemia Protein
149025-06-9
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Kmt2a protein, mouse
EC 2.1.1.43
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009250Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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