Associates with chromatin regions downstream of transcriptional start sites of active genes and thus regulates gene transcription (By similarity). Chromatin interaction is mediated via the binding to tri-methylated histone H3 at 'Lys-4' (H3K4me3) (By similarity). Key regulator of hematopoiesis involved in terminal myeloid differentiation and in the regulation of hematopoietic stem cell (HSCs) self-renewal by a mechanism that involves DNA methylation (PubMed:18854576, PubMed:18952892, PubMed:18818388). Also acts as an important cell cycle regulator, participating in cell cycle regulatory network machinery at multiple cell cycle stages including G1/S transition, S phase progression and mitotic entry (PubMed:19264965). Recruited to E2F1 responsive promoters by HCFC1 where it stimulates tri-methylation of histone H3 at 'Lys-4' and transcriptional activation and thereby facilitates G1 to S phase transition (By similarity). During myoblast differentiation, required to suppress inappropriate expression of S-phase-promoting genes and maintain expression of determination genes in quiescent cells (PubMed:19264965). Component of a complex composed of KMT2E, OGT and USP7; the complex stabilizes KMT2E, preventing KMT2E ubiquitination and proteosomal-mediated degradation. Interacts (via N-terminus) with OGT (via TRP repeats). Interacts with deubiquitinating enzyme USP7 (via MATH domain). Interacts (via HBM motif) with HCFC1 (via Kelch domain). Interacts with E2F1; the interaction is probably indirect and is mediated via HCFC1. Absent from the nucleolus. Localizes to chromosome during interphase and to centrosomes during mitosis. Dissociation from mitotic chromosome is likely due to histone H3 phosphorylation on 'Thr-3' and 'Thr-6'. Up-regulated in reversibly arrested C2C12 myoblasts. The PHD-type domain binds specifically histone H3 tri-methylated at 'Lys-4' (H3K4me3), thus promoting binding to chromatin. The SET domain does not bind the methyl group donor S-adenosyl-L-methionine and histone 3 H3K4 peptide as a large loop prevents the docking of the 'Lys-4' side chain. The C-terminus domain is responsible for the localization to the centrosome during mitosis. Ubiquitinated. Deubiquitinated by USP7. O-glycosylated at Ser-435 and Thr-440 in the SET domain by OGT which probably prevents KMT2E proteosomal-mediated degradation. Defects in immunity and hematopoiesis. Adult homozygous mice are obtained at reduced frequency because of postnatal lethality. Surviving animals display a variety of abnormalities, including male infertility, retarded growth and defects in multiple hematopoietic lineages. They also show increased susceptibility to spontaneous eye infections associated with a cell-autonomous impairment of neutrophil function. They exhibit a mild impairment of erythropoiesis and hematopoietic stem cells (HSCs) have impaired competitive repopulating capacity both under normal conditions and when subjected to self-renewal stimulation by NUP98-HOXA10. Homozygous HSCs show a dramatic sensitivity to DNA demethylation-induced differentiation (5-azadeoxycytidine). Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. TRX/MLL subfamily. Does not exhibit histone methyltransferase towards histone H3 in vitro (PubMed:18952892). The isolated catalytic SET domain lacks binding activity towards cofactor S-adenosyl-L-methionine; instead of the highly conserved XGXG, Y and NH motifs, KMT2E displays NKKI (Asn-339-Ile-342), F (Phe-381) and RR (Arg-408-Arg-409) motifs. Also lacks binding activity towards histone H3 due to a poor conservation of the key residues involved in the binding and the presence of large loop which prevents the docking of the H3 'Lys-4' side chain. Contaminating sequence. Potential poly-A sequence starting in position 486. Contaminating sequence. Potential poly-A sequence starting in position 803. Contaminating sequence. Potential poly-A sequence starting in position 495. Contaminating sequence. Potential poly-A sequence starting in position 492.