2024-05-29

Abstract:

MLL/SET/COMPASS methyltransferase complexes catalyze the methylation of histone 3 lysine 4 (H3K4) and play critical roles in development and cancer. H3K4 trimethylation is one of the most studied epigenetic modifications and is highly enriched at the transcriptional start site of actively transcribing genes. While mammals possess 6 homologs of the yeast H3K4 methyltransferase SET1, the extent to which their cellular functions result from enzymatic activity remains unclear. One of the most well-characterized SET1 homologs is MLL1, which is found in fusion proteins generated by chromosomal translocation of the MLL1 gene in pediatric acute leukemia cases. However, the catalytic domain of the MLL1 protein is dispensable for leukemia growth, suggesting a non-catalytic function of wild-type MLL1 and possible redundancies among other SET1 homologs contributing to H3K4 methylation. To explore the roles of H3K4 methyltransferase complexes in leukemia, we conducted functional screening against MLL/SET/COMPASS complex subunits and identified the essential and non-redundant roles of SETD1A/SETD1B SET1 homologs. Additionally, we revealed the non-catalytic function and a novel protein complex of SETD1A which can directly modulate RNA polymerase. Recent studies and our report have indicated that non-enzymatic functions are targetable by utilizing a PROTAC-mediated degradation. In this seminar, I will introduce the canonical and non-canonical roles of H3K4 methyltransferases in leukemia and development and discuss their potential as therapeutic targets for leukemia and other tumors.

References:

1. Perlee S, Kikuchi S, Nakadai T, Masuda T, Ohtsuki S, Matsumoto M, Rahmutulla B, Fukuyo M, Cifani P, Kentsis A, Roeder RG, Kaneda A, Hoshii T*. SETD1A function in leukemia is mediated through interaction with mitotic regulators BuGZ/BUB3. EMBO Rep. 2023 Oct 9;24(10):e57108.

2. Hoshii T*, Perlee S, Kikuchi S, Rahmutulla B, Fukuyo M, Masuda T, Ohtsuki S, Soga T, Nabet B, Kaneda A. SETD1A regulates transcriptional pause release of heme biosynthesis genes in leukemia. Cell Reports. 2022 Nov 29;41(9):111727.

3. Yang L, Chan AKN, Miyashita K, Delaney CD, Wang X, Li H, Pokharel SP, Li S, Li M, Xu X, Lu W, Liu Q, Mattson N, Chen KY, Wang J, Yuan YC, Horne D, Rosen ST, Soto-Feliciano Y, Feng Z, Hoshii T, Xiao G, Müschen M, Chen J, Armstrong SA, Chen CW. High-resolution characterization of gene function using single-cell CRISPR tiling screen. Nat Commun. 2021 Jul 1;12(1):4063.

4. Hoshii T, Cifani P, Feng Z, Huang CH, Koche R, Chen CW, Delaney CD, Lowe SW, Kentsis A, Armstrong SA. A non-catalytic function of SETD1A regulates Cyclin-K and the DNA damage response. Cell. 2018 Feb 22;172(5):1007-1021.e17.