Epigenetic regulation by WDR5-containing histone modifying complexes

The WDR5 histone methyltransferase complexes (KMT2 complexes) include the Mixed Lineage Leukemia (MLL) 1-4, SET1A, and SET1B. All KMT2 complexes consist of a histone methyltransferase (KMT2A, KMT2B, KMT2C, KMT2D, SETD1A, or SETD1B, respectively) and the WRAD subcomplex composed of WDR5, RBBP5, ASH2L, and DPY30. The WRAD complex regulates the enzymatic activity of histone methyltransferases and enables their recruitment to chromatin. Additional transcription cofactors associate with each KMT2 histone methyltransferase complex, enabling their functional diversification. All KMT2 complexes methylate lysine K5 of histone H3 (K4 in mature histone H3 peptides, as the initiator methionine is removed), which is associated with transcriptional activation. Different KMT2 complexes preferentially monomethylate, dimethylate, or trimethylate H3K4, depending on the presence of accessory subunits, transcriptional co-factors, and posttranslational modifications. The KMT2A and KMT2B complexes preferentially methylate H3K4 at a limited number of target gene promoters, while KMT2C and KMT2D complexes preferentially methylate H3K4 at a limited number of target gene enhancers. SETD1A and SETD1B complexes are responsible for the bulk of cellular H3K4 methylation and show less target specificity. For a detailed overview, please refer to Cho et al. 2007, Song and Kingston 2008, Patel et al. 2009, Wang et al. 2009, Takahashi et al. 2011, Couture and Skiniotis 2013, van Nuland et al. 2013, Rao and Dou 2015, Klonou et al. 2021.

WDR5 is also a component of three histone acetyltransferase complexes, GCN5-ATAC, PCAF-ATAC, and MOF/KAT8-NSL. The role of WDR5 in epigenetic regulation of gene expression through histone acetylation is under investigation (reviewed in Guarnaccia and Tansey 2018).

The KMT2C (MLL3) complex, together with the related KMT2D (MLL4) complex, is most similar to Drosophila Trr (Trithorax-related) and mediates hitone H3 lysine-4 (H3K4 - lysine 5 in nascent histone H3) monomethylation, with the establishment of the H3K4me1 epigenetic marks, at transcription enhancers throughout the human genome, with estimates ranging from approximately 12,000 to over 20,000 sites, depending on the cell type and developmental stage. While H3K4 monomethylation by MLL3 and MLL4 complexes may not be essential for expression of developmental genes, it is likely important for fine tuning of transcription levels and timing, both during normal development and in cancer. For review, please refer to Hu et al. 2013, Piunti and Shilatifard 2016, Fagan and Dingwall 2019, and Klonou et al. 2021.

Based on mouse studies, MLL3 and MLL4 complexes play an important role in adipogenesis and myogenesis. During adipogenesis, the KMT2D (MLL4) complex preferentially localizes to active enhancers, marked by the presence of mono- or dimethylated histone H3 lysine-4 (H3K4me1/2, residue K4 corresponds to residue K5 in nascent histone H3), acetylated H3 lysine-27 (H3K27ac), and the presence of RNA Pol II. KMT2D localizes to these active enhancers together with the adipogenic transcription factors CEBPB, CEBPA, and PPARG, and is especially enriched at high confidence enhancers that are both CEBP and PPARG positive.