RT Journal
A1 Han, Xingmin
A1 Xu, Chenghui
A1 Ren, Yiyi
A1 Guo, Meiling
A1 Yan, Jiayue
A1 Wang, Xuan
A1 Liu, Chao
A1 Gu, Qin
A1 Shen, Xing-Xing
A1 Ma, Zhonghua
A1 Chen, Yun
T1 Synergistic regulation by H3K36 and H3K27 methylation defines the chromatin landscape to control virulence and secondary metabolism in a fungal pathogen
JF Genome Research 
JO Genome Research 
YR 2025 
FD November 01 
VO 35 
IS 11 
SP 2472 
OP 2487 
DO 10.1101/gr.280560.125 
UL http://genome.cshlp.org/content/35/11/2472.abstract 
AB Histone methylation, catalyzed by SET domain-containing lysine methyltransferases, is a conserved epigenetic mechanism regulating gene expression in eukaryotes. However, the evolutionary dynamics of SET domain proteins and their functional interplay in fungi remain poorly understood. Here, we analyzed 18,718 SET domain proteins from 1038 fungal genomes and identified three major clusters, with Cluster 1 enriched for canonical histone methyltransferases. The evolution of the SET domain protein family coordinates with genome expansion in fungi. Functional characterization of seven Cluster 1 proteins in Fusarium graminearum, a globally significant fungal pathogen, reveals diverse roles in growth, development, and virulence. In-depth analyses of two H3K36-specific methyltransferases, Set2 and Ash1, uncover their distinct regulatory functions. Set2-mediated H3K36me3 is enriched in gene bodies of euchromatic regions and facilitates transcription elongation. In contrast, Ash1-mediated H3K36me3 localizes to promoters within facultative heterochromatin and represses transcription. Notably, Ash1-mediated H3K36me3 cooperates with Polycomb repressive complex 2 (PRC2)-dependent H3K27me3 to silence secondary metabolite (SM) gene clusters. Deletion of ASH1 reduces H3K27me3 levels and derepresses SM gene expression. Conversely, Set2-mediated H3K36me3, facilitated by Ctk1-dependent RNA polymerase II phosphorylation, promotes transcriptional elongation of SM genes. Together, these findings reveal evolutionary features of fungal SET domain proteins and uncover a synergistic interplay between H3K36me3 and H3K27me3 in regulating fungal secondary metabolism and virulence. This study advances our understanding of epigenetic regulation in fungi and provides potential targets for controlling fungal pathogens.