The COMPASS family of histone H3K4 methylases: mechanisms of regulation in development and disease pathogenesis

Abstract

The Saccharomyces cerevisiae Set1/COMPASS was the first histone H3 lysine 4 (H3K4) methylase identified over 10 years ago. Since then, it has been demonstrated that Set1/COMPASS and its enzymatic product, H3K4 methylation, is highly conserved across the evolutionary tree. Although there is only one COMPASS in yeast, Drosophila possesses three and humans bear six COMPASS family members, each capable of methylating H3K4 with nonredundant functions. In yeast, the histone H2B monoubiquitinase Rad6/Bre1 is required for proper H3K4 and H3K79 trimethylations. The machineries involved in this process are also highly conserved from yeast to human. In this review, the process of histone H2B monoubiquitination-dependent and -independent histone H3K4 methylation as a mark of active transcription, enhancer signatures, and developmentally poised genes is discussed. The misregulation of histone H2B monoubiquitination and H3K4 methylation result in the pathogenesis of human diseases, including cancer. Recent findings in this regard are also examined.

Figure 1. Chromatin, histone modifications and gene expression

The very long eukaryotic DNA is compacted within the cell nucleus through its interactions with histones, forming the nucleosomes. Structural studies of nucleosomes demonstrated that the histone N-terminal tails protrude outward beyond the gyres of the DNA. Many of the amino acid residues within the histone tails can be posttranslationally modified providing a landing pad for a diverse array of transcription factors, chromatin remodelers and DNA- interacting proteins to regulate gene expression. In this figure, sites of posttranslational modifications on histone tails for H3K4 methylation and H2B monoubiquitination by the COMPASS family and the Rad6/Bre1 complex, respectively, are shown.

Figure 2. The subunit composition of the COMPASS family from yeast to human

The yeast Set1/COMPASS is the founding member of the family of COMPASS H3K4 methyltransferases. There is only one Set1/COMPASS in yeast capable of methylating histone H3 on its fourth lysine (H3K4). From yeast to Drosophila, COMPASS is divided into three family members. The Set1/COMPASS of Drosophila is the direct descendent of the yeast Set1 complex (shown by solid arrow). There are two COMPASS-like complexes in Drosophila (shown by dotted arrow); one Trithorax (trx)-containing complex and the other Trithorax-related-containing complex (trr). The SET domain-containing enzymes from yeast to Drosophila are shown in RED, and the conserved subunits between yeast and Drosophila are shown in GREEN. The complex specifics are shown in BLUE and PURPLE. From Drosophila to human cells, the COMPASS family is divided into six members. The mammalian Set1A and B are direct homologs of yeast and Drosophila Set1 and are found in Set1A-B/COMPASS (shown by solid arrow). The subunit composition and function of Trx of Drosophila is divided between MLL1 and MLL2 in the mammalian cells. Both MLL1 and MLL2 are found in COMPASS-like complexes. The subunit composition and function of Trr of Drosophila is divided between MLL3 and MLL4 in the mammalian cells, both of which are also found in COMPASS-like complexes. All six mammalian COMPASS family members are capable of methylating H3K4. The known common subunits shared between yeast, Drosophila and the human complexes are shown in GREEN. Cps35 in yeast and Drosophila and its homolog of mammalian Wdr82 shown in BLUE, are found only in Set1A-B/COMPASS. Menin shown in BLUE is found in complex with Trx and the MLL1-2/COMPASS-like complexes. The shared subunits among the trr and the MLL3-4 complexes, Utx, PTIP, PA1 and NCOA6 are shown in PURPLE.

Figure 3. MLL translocation into Super Elongation Complex in leukemic pathogenesis

The MLL gene is found in a variety of chromosomal translocations associated with childhood leukemia. The ELL protein was the first translocation partner of MLL for which a biological function was demonstrated. Biochemically, ELL was identified as a RNA polymerase II elongation factor and it was proposed then that the elongation stage of transcription could be central in the pathogenesis of leukemia through MLL translocations. We now know that many of the MLL translocation partners such as ENL, AF9, AFF1, AFF4 are found in a super elongation complex (SEC) with ELL and the RNA polymerase II elongation factor P-TEFb. It has been proposed that the translocation of MLL into SEC results in the mistargeting of SEC to MLL-regulated genes and the misregulating of their expression without appropriate transcriptional elongation checkpoints.