Histone methyltransferase that plays an essential role in early development and hematopoiesis (By similarity). Catalytic subunit of the MLL1/MLL complex, a multiprotein complex that mediates both methylation of 'Lys-4' of histone H3 (H3K4me) complex and acetylation of 'Lys-16' of histone H4 (H4K16ac) (By similarity). Catalyzes methyl group transfer from S-adenosyl-L-methionine to the epsilon-amino group of 'Lys-4' of histone H3 (H3K4) via a non-processive mechanism. Part of chromatin remodeling machinery predominantly forms H3K4me1 and H3K4me2 methylation marks at active chromatin sites where transcription and DNA repair take place (By similarity). Has weak methyltransferase activity by itself, and requires other component of the MLL1/MLL complex to obtain full methyltransferase activity (By similarity). Has no activity toward histone H3 phosphorylated on 'Thr-3', less activity toward H3 dimethylated on 'Arg-8' or 'Lys-9', while it has higher activity toward H3 acetylated on 'Lys-9' (By similarity). Binds to unmethylated CpG elements in the promoter of target genes and helps maintain them in the nonmethylated state (By similarity). Required for transcriptional activation of HOXA9 (By similarity). Promotes PPP1R15A-induced apoptosis (By similarity). Plays a critical role in the control of circadian gene expression and is essential for the transcriptional activation mediated by the CLOCK-ARNTL/BMAL1 heterodimer (PubMed:21113167). Establishes a permissive chromatin state for circadian transcription by mediating a rhythmic methylation of 'Lys-4' of histone H3 (H3K4me) and this histone modification directs the circadian acetylation at H3K9 and H3K14 allowing the recruitment of CLOCK-ARNTL/BMAL1 to chromatin (PubMed:21113167). Also has auto-methylation activity on Cys-3879 in absence of histone H3 substrate (By similarity). L-lysyl(4)-[histone H3] + S-adenosyl-L-methionine = H(+) + N(6)-methyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-homocysteine N(6)-methyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-methionine = H(+) + N(6),N(6)-dimethyl-L-lysyl(4)-[histone H3] + S-adenosyl-L-homocysteine L-cysteinyl-[protein] + S-adenosyl-L-methionine = H(+) + S-adenosyl-L-homocysteine + S-methyl-L-cysteinyl-[protein] MLL cleavage product N320 heterodimerizes with MLL cleavage product C180 (via SET and FYRC domains). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, HCFC2, WDR5, DPY30 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MEN1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10. Interacts (via WIN motif) with WDR5; the interaction is direct. Interaction with WDR5 is required for stable interaction with ASH2L and RBBP5, and thereby also for optimal histone methyltransferase activity. Interacts with KAT8/MOF; the interaction is direct. Interacts with SBF1 and PPP1R15A. Interacts with ZNF335 (By similarity). Interacts with CLOCK and ARNTL/BMAL1 in a circadian manner (PubMed:21113167). Interacts with PPIE; this results in decreased histone H3 methyltransferase activity. Interacts with CREBBP (By similarity). Interacts with the WRAD complex composed of WDR5, RBBP5, ASH2L and DPY30 (By similarity). Interacts (via MBM motif) with MEN1 (By similarity). Interacts (via IBM motifs) with PSIP1 (via IBD domain) with moderate affinity whereas the KMT2A-MEN1 complex interacts with a greater affinity; MEN1 enhances interaction of KMT2A with PSIP1 (By similarity). Phosphorylation increases its affinity for PSIP1 (By similarity). Forms a complex with CREBBP and CREB1 (By similarity). Localizes to a diffuse nuclear pattern when not associated with MLL cleavage product N320. The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors. The SET domain structure is atypical and is not in an optimal position to have methyltransferase activity. It requires other components of the MLL1/MLL complex, such as ASH2L or RBBP5, to order the active site and obtain optimal histone methyltransferase activity. The CXXC-type zinc finger binds to DNA sequence elements containing unmethylated CpG dinucleotides. The third PHD-type zinc-finger binds both trimethylated histone H3K4me3 and PPIE; histone and PPIE bind to distinct surfaces. Nevertheless, PPIE binding and histone binding are mutually inhibitory. Isomerization of a peptidylproline bond in the linker between the third PHD-type zinc-finger and the bromo domain disrupts the interaction between the bromo domain and the third PHD-type zinc-finger, and thereby facilitates interaction with PPIE. Proteolytic cleavage by TASP1 generates MLL cleavage 3product N320 and MLL cleavage product C180, which reassemble through a non-covalent association. 2 cleavage sites exist, cleavage site 1 (CS1) and cleavage site 2 (CS2), to generate MLL cleavage products N320 and C180. CS2 is the major site. Phosphorylation increases its interaction with PSIP1. Auto-methylated at Cys-3879: auto-methylation is inhibited by the WRAD complex and unmodified histone H3. Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. TRX/MLL subfamily. Truncated N-terminus.