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BRWD3 promotes KDM5 degradation to maintain H3K4 methylation levels

ABSTRACT: Histone modifications are critical for regulating chromatin structure and gene expression. Dysregulation of histone modifications likely contributes to disease states and cancer. Depletion of the chromatin-binding protein BRWD3, a known substrate-specificity factor of the Cul4-DDB1 E3 ubiquitin ligase complex, results in increased in H3K4me1 levels. The underlying mechanism linking BRWD3 and H3K4 methylation, however, has yet to be defined. Here, we show that depleting BRWD3 not only causes an increase in H3K4me1 levels, but also causes a decrease in H3K4me3 levels, indicating that BRWD3 influences H3K4 methylation more broadly. Using immunoprecipitation coupled to quantitative mass spectrometry, we identified an interaction between BRWD3 and the H3K4-specific demethylase 5 (KDM5/Lid), an enzyme that removes tri- and di- methyl marks from H3K4. Moreover, analysis of ChIP-seq data revealed that BRWD3 and KDM5 are significantly co-localized throughout the genome and that sites of H3K4me3 are highly enriched at BRWD3 binding sites. We show that BRWD3 promotes K48-linked polyubiquitination and degradation of KDM5 and that KDM5 degradation is dependent on both BRWD3 and Cul4. Critically, depleting KDM5 fully restores altered H3K4me3 levels and partially restores H3K4me1 levels upon BRWD3 depletion. Together, our results demonstrate that BRWD3 regulates KDM5 activity to balance H3K4 methylation levels.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE236629 | GEO | 2024/09/30

REPOSITORIES: GEO

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BRWD3 targets KDM5/Lid for degradation to maintain H3K4 methylation levels

Project description:Histone modifications are critical for regulating chromatin structure and gene expression. Dysregulation of histone modification levels may contribute to disease development and cancer. Therefore, understanding histone modifications is essential for development and disease. The chromatin-binding protein BRWD3, a known substrate-specificity factor of the Cul4-DDB1 E3 ubiquitin ligase complex, is required for maintaining active histone modification levels. Loss of BRWD3 function causes an increase in H3K4me1 levels. The underline mechanism, however, is unknown. We found that BRWD3 depletion also causes a decrease in H3K4me3 levels. To reveal the mechanism by which BRWD3 regulates the H3K4 methylation levels, we performed BRWD3-IP mass-spectrometry. We identified an interaction between BRWD3 and the lysine-specific demethylase 5 (KDM5/Lid), an enzyme that removes tri- and di- methyl marks from lysine 4 on histone H3. Moreover, analysis of ChIP-seq data revealed that BRWD3 and KDM5 are significantly co-localized throughout the genome. We show that BRWD3 promotes K48-linked ubiquitination of KDM5. Consistent with this, KDM5/Lid is rapidly degraded in a proteasome-dependent manner with a half-life of less than 30 mins. Critically, KDM5/Lid degradation is dependent on both BRWD3 and Cul4. In addition, we have found that BRWD3 is suppressor of Position-effect variegation (PEV). Loss of a single copy of KDM5, however, partially rescues the the BRWD3 PEV phenotype. Our results suggest that BRWD3 targets KDM5/Lid for degradation to ensure the balance of H3K4me levels.

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BRWD3 promotes KDM5 degradation to maintain H3K4 methylation levels

Project description:BRWD3 promotes KDM5 degradation to maintain H3K4 methylation levels

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