Structural insights into the recognition of histone H3Q5 serotonylation by WDR5

Abstract

Serotonylation of histone H3Q5 (H3Q5ser) is a recently identified posttranslational modification of histones that acts as a permissive marker for gene activation in synergy with H3K4me3 during neuronal cell differentiation. However, any proteins that specifically recognize H3Q5ser remain unknown. Here, we found that WDR5 interacts with the N-terminal tail of histone H3 and functions as a “reader” for H3Q5ser. Crystal structures of WDR5 in complex with H3Q5ser and H3K4me3Q5ser peptides revealed that the serotonyl group is accommodated in a shallow surface pocket of WDR5. Experiments in neuroblastoma cells demonstrate that H3K4me3 modification is hampered upon disruption of WDR5-H3Q5ser interaction. WDR5 colocalizes with H3Q5ser in the promoter regions of cancer-promoting genes in neuroblastoma cells, where it promotes gene transcription to induce cell proliferation. Thus, beyond revealing a previously unknown mechanism through which WDR5 reads H3Q5ser to activate transcription, our study suggests that this WDR5-H3Q5ser–mediated epigenetic regulation apparently promotes tumorigenesis.

The Expanding Constellation of Histone Post-Translational Modifications in the Epigenetic Landscape

“…Concurrently, the H3K4me2/3 demethylases LSD1 and KDM5B/C are profoundly inhibited by the presence of the neighbouring H3Q5ser [174]. Most notably, deposition of the H3K4me3 mark is hampered upon disruption of the interaction between H3Q5ser and WDR5, which is a core subunit of the H3K4-specific MLL1 methyltransferase complex [174,175]. Taken together, these findings suggest that H3Q5ser is required to impose H3K4me3 and to stabilize it from dynamic turnover, enhancing its physical readout by downstream effectors.…”

“…The H3Q5ser mark was found to coexist with adjacent H3K4me3 on the same histone tail at euchromatic regions of active gene expression in differentiating serotonergic neurons [168]. In this chromatin context, the TAF3 subunit of TFIID, normally involved in the recognition of H3K4me3, exhibits stronger binding preference for the H3K4me3Q5ser dual modification [172][173][174]. Concurrently, the H3K4me2/3 demethylases LSD1 and KDM5B/C are profoundly inhibited by the presence of the neighbouring H3Q5ser [174].…”

“…In this chromatin context, the TAF3 subunit of TFIID, normally involved in the recognition of H3K4me3, exhibits stronger binding preference for the H3K4me3Q5ser dual modification [172][173][174]. Concurrently, the H3K4me2/3 demethylases LSD1 and KDM5B/C are profoundly inhibited by the presence of the neighbouring H3Q5ser [174]. Most notably, deposition of the H3K4me3 mark is hampered upon disruption of the interaction between H3Q5ser and WDR5, which is a core subunit of the H3K4-specific MLL1 methyltransferase complex [174,175].…”

Clustered PHD domains in KMT2/MLL proteins are attracted by H3K4me3 and H3 acetylation-rich active promoters and enhancers

“…KMT2A-D proteins are recruited to their chromatin targets not only by their reading domains but their localization can also be influenced by their association with other chromatin reader subunits of hCOMPASS-like complexes. For WDR5, a preference for methylated H3K4, particularly dimethylated H3K4 [14,55,56] with modulation by methylation of H3R2 [19] and serotonylation of H3Q5, was demonstrated biochemically [57]. For ASH2L, strong evidence for DNA binding was shown [18,58].…”

Genome-Wide ChIP-seq and RNA-seq Analyses of STAT3 Target Genes in TLRs Activated Human Peripheral Blood B Cells

“…ChIP assay was carried out as previous studies ( 15 , 16 ). Briefly, after crosslinking chromatin with 1% formaldehyde for 10 min and neutralizing with 0.125 M glycine for 5 min at room temperature, cells were washed with cold PBS, and lysed in cold lysis buffer on ice.…”