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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 <jats:italic>Mll1<\/jats:italic>-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 <jats:italic>Pitx1<\/jats:italic>, <jats:italic>Pitx2<\/jats:italic>, <jats:italic>Foxa1<\/jats:italic>, <jats:italic>Gata4<\/jats:italic>, <jats:italic>Zfp503<\/jats:italic> and <jats:italic>Onecut2<\/jats:italic>, as well as the H3K27me3 binder, <jats:italic>Bahcc1<\/jats:italic>. 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.<\/jats:p>","DOI":"10.1371\/journal.pgen.1009250","type":"journal-article","created":{"date-parts":[[2021,12,3]],"date-time":"2021-12-03T18:28:07Z","timestamp":1638556087000},"page":"e1009250","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":18,"title":["MLL1 is required for maintenance of intestinal stem cells"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2531-5514","authenticated-orcid":true,"given":"Neha","family":"Goveas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3261-0922","authenticated-orcid":true,"given":"Claudia","family":"Waskow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Arndt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Heuberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8292-938X","authenticated-orcid":true,"given":"Qinyu","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3715-1756","authenticated-orcid":true,"given":"Dimitra","family":"Alexopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Dahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Birchmeier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9814-0559","authenticated-orcid":true,"given":"Konstantinos","family":"Anastassiadis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4754-1707","authenticated-orcid":true,"given":"A. 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Slany","year":"2009","journal-title":"Haematologica"},{"issue":"6","key":"pgen.1009250.ref024","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1038\/onc.2008.443","article-title":"Alterations of the CxxC domain preclude oncogenic activation of mixed-lineage leukemia 2","volume":"28","author":"C Bach","year":"2009","journal-title":"Oncogene"},{"issue":"3","key":"pgen.1009250.ref025","doi-asserted-by":"crossref","first-page":"194503","DOI":"10.1016\/j.bbagrm.2020.194503","article-title":"MLL fusion proteins and transcriptional control","volume":"1863","author":"RK Slany","year":"2020","journal-title":"Biochim Biophys Acta Gene Regul Mech"},{"issue":"6","key":"pgen.1009250.ref026","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1016\/j.molcel.2010.05.011","article-title":"Multiple interactions recruit MLL1 and MLL1 fusion proteins to the HOXA9 locus in leukemogenesis","volume":"38","author":"TA Milne","year":"2010","journal-title":"Mol Cell"},{"issue":"1","key":"pgen.1009250.ref027","doi-asserted-by":"crossref","first-page":"4256","DOI":"10.1038\/s41467-019-12086-9","article-title":"MLL1 is required for PAX7 expression and satellite cell self-renewal in mice","volume":"10","author":"GC Addicks","year":"2019","journal-title":"Nat Commun"},{"issue":"6486","key":"pgen.1009250.ref028","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1126\/science.aba5960","article-title":"Maintenance of neural stem cell positional identity by mixed-lineage leukemia 1","volume":"368","author":"RN Delgado","year":"2020","journal-title":"Science"},{"issue":"2","key":"pgen.1009250.ref029","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.cell.2013.07.004","article-title":"The intestinal crypt, a prototype stem cell compartment","volume":"154","author":"H Clevers","year":"2013","journal-title":"Cell"},{"issue":"7165","key":"pgen.1009250.ref030","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1038\/nature06196","article-title":"Identification of stem cells in small intestine and colon by marker gene Lgr5","volume":"449","author":"N Barker","year":"2007","journal-title":"Nature"},{"issue":"1","key":"pgen.1009250.ref031","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/s41575-018-0081-y","article-title":"Tales from the crypt: new insights into intestinal stem cells","volume":"16","author":"H Gehart","year":"2019","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"10","key":"pgen.1009250.ref032","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1128\/MCB.06288-11","article-title":"A critical role for the Wnt effector Tcf4 in adult intestinal homeostatic self-renewal","volume":"32","author":"JH van Es","year":"2012","journal-title":"Mol Cell 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Hematol"},{"issue":"2","key":"pgen.1009250.ref039","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.tcb.2014.09.003","article-title":"Plasticity within stem cell hierarchies in mammalian epithelia","volume":"25","author":"PW Tetteh","year":"2015","journal-title":"Trends Cell Biol"},{"issue":"13","key":"pgen.1009250.ref040","doi-asserted-by":"crossref","first-page":"5940","DOI":"10.1073\/pnas.92.13.5940","article-title":"Ligand-regulated site-specific recombination","volume":"92","author":"C Logie","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"6","key":"pgen.1009250.ref041","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1093\/nar\/26.6.1427","article-title":"Temporally and spatially regulated somatic mutagenesis in mice","volume":"26","author":"F Schwenk","year":"1998","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"pgen.1009250.ref042","doi-asserted-by":"crossref","first-page":"e12","DOI":"10.1093\/nar\/gng012","article-title":"Rapid generation of inducible mouse mutants","volume":"31","author":"J Seibler","year":"2003","journal-title":"Nucleic Acids Res"},{"key":"pgen.1009250.ref043","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0076-6879(10)77008-7","article-title":"A recombineering pipeline to make conditional targeting constructs","volume":"477","author":"J Fu","year":"2010","journal-title":"Methods Enzymol"},{"issue":"3","key":"pgen.1009250.ref044","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1002\/gene.20012","article-title":"A reliable lacZ expression reporter cassette for multipurpose, knockout-first alleles","volume":"38","author":"G Testa","year":"2004","journal-title":"Genesis"},{"issue":"3","key":"pgen.1009250.ref045","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1242\/dev.102681","article-title":"Mll2 is required 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Yan","year":"2017","journal-title":"Cell Stem Cell"},{"issue":"13","key":"pgen.1009250.ref052","doi-asserted-by":"crossref","first-page":"5097","DOI":"10.1523\/JNEUROSCI.3004-14.2015","article-title":"Neuronal Kmt2a\/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory","volume":"35","author":"M Jakovcevski","year":"2015","journal-title":"J Neurosci"},{"issue":"13","key":"pgen.1009250.ref053","doi-asserted-by":"crossref","first-page":"3103","DOI":"10.1038\/npp.2016.144","article-title":"Neuronal Deletion of Kmt2a\/Mll1 Histone Methyltransferase in Ventral Striatum is Associated with Defective Spike-Timing-Dependent Striatal Synaptic Plasticity, Altered Response to Dopaminergic Drugs, and Increased Anxiety","volume":"41","author":"EY 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