Methylation of histone 3 on lysine 4 (H3K4) is one of the most conserved and widespread epigenetic systems. H3K4 is methylated in euchromatic regions, with trimethylated H3K4 (H3K4me3) on nucleosomes surrounding active promoters, H3K4me2 marking transcribed regions and H3K4me1 relating to enhancers and active chromatin in general. Mammals have six Set1/Trithorax-related methyltransferases that are encoded by three pairs of paralogous sister genes namely, Mll1 (Kmt2a) and Mll2 (Kmt2b), Mll3 (Kmt2c) and Mll4 (Kmt2d), Setd1a (Kmt2f) and Setd1b (Kmt2g). We have been studying all six using conditional mutagenesis in the mouse. The contrasting and overlapping roles of the H3K4 system will be discussed with emphasis on recent progress.
MLL1 (mixed lineage leukemia) was discovered as the causative mutation in early onset leukemia. In development it is first required for definitive hematopoiesis and then hematopoietic stem cell maintenance. We found 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 a loss of ISCs and a differentiation bias towards the secretory lineage with increased numbers and enlargement of goblet cells. Transcriptome analyses of ISCs, Paneth cells and intestinal organoids implicate MLL1-dependent expression in ISCs of several transcription factors including Pitx2, Foxa1, Gata4, Zfp503, Pitx1, Onecut2 and the H3K27me3 binder Bahcc1. We add ISCs to the MLL1 repertoire and observe that all known postnatal functions of MLL1 relate to stem cell maintenance thereby highlighting the suggestion that MLL1 is a master stem cell regulator. In contrast, MLL4, which is prominently mutated in many cancers, is first required for migration of the anterior visceral endoderm to establish the anterior-posterior axis in the early embryo.