Chromatin control of gene expression: Mixed-lineage leukemia methyltransferase SETs the stage for transcription

Mixed-lineage leukemia recruitment absolutely depends on active transcription.

DNA is tightly packaged inside the nucleus into chromatin, an intricate assembly of nucleic acid, histones, and accessory proteins. Under normal circumstances, the higher-order structure of chromatin is a formidable obstacle for almost all biochemical processes that involve DNA. To enable transcription, replication, and repair, all eukaryotic cells possess a whole array of sophisticated molecular machines with the sole purpose of modifying chromatin structure to allow unhindered access to DNA. Next to ATP-powered units that literally push nucleosomes out of the way, there are many enzymes that catalyze the covalent modification of histones. The various methylations, acetylations, phosphorylations, and ubiquitinations either directly change the packaging properties of the histone octamer or mark these proteins for recognition by other proteins that help to read out this so-called “histone code” (1). A flurry of recent publications describes an ever-growing list of histone modifications, the associated enzymes, and the respective correlation with an “activated” or “repressed” chromatin state. Still, important questions remain. For example, it is well established that histones in actively transcribed regions are acetylated and have a certain methylation pattern. However, we have no clue how modification activities are specifically recruited to coding regions that need to be transcribed. We comprehend neither what happens if a gene must be switched off nor how an enzyme “knows” where a gene starts and where it ends. In this issue of PNAS, Milne et al. (2) begin to address these questions in an elegant system involving the histone H3 lysine 4-specific methyltransferase mixed-lineage leukemia (MLL).

The MLL gene has become notorious because of its frequent involvement in chromosomal translocations (11q23 translocations) that lead …