Regulation of transcription by the MLL2 complex and MLL complex-associated AKAP95

Although histone H3 lysine 4 (H3K4) methylation is widely associated with gene activation, direct evidence for its causal role in transcription, through specific MLL family members, is scarce. Here we have purified a human MLL2 (Kmt2b) complex that is highly active in H3K4 methylation and chromatin transcription in a cell-free system. This effect requires SAM and intact H3K4, establishing a direct and causal role for MLL2-mediated H3K4 methylation in transcription. We then show that human AKAP95, a chromatin-associated protein, is physically and functionally associated with the DPY30–MLL complexes and directly enhances their methyltransferase activity. Ectopic AKAP95 stimulates expression of a chromosomal reporter in synergy with MLL1 or MLL2, whereas AKAP95 depletion impairs retinoic acid-mediated gene induction in embryonic stem cells. These results demonstrate an important role for AKAP95 in regulating histone methylation and gene expression, particularly during cell fate transitions.