Journal
SCIENCE ADVANCES
Volume 7, Issue 25, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abf4291
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Funding
- Chinese Academy of Sciences, Strategic Priority Research Program [XDB37010105]
- National Key Research and Development Program of China [2017YFA0503600, 2016YFA0400903]
- National Natural Science Foundation of China Foundation, Innovative Research Groups [31621002]
- National Natural Science Foundation of China [91853133, 82002662]
- Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics [20dz2260900]
- USTC Research Funds of the Double First-Class Initiative [YD2070002015]
- Fundamental Research Funds for the Central Universities [WK2070000150, WK2070000171]
- Science and Technology Commission of Shanghai Municipality [18ZR1424500]
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The study identified that WDR5 interacts with histone H3Q5ser and functions as a reader for H3Q5ser, promoting gene transcription and cell proliferation in neuroblastoma cells. The WDR5-H3Q5ser-mediated epigenetic regulation appears to promote tumorigenesis by activating gene transcription.
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.
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