组蛋白修饰对调控染色质结构和基因表达至关重要。组蛋白修饰的失调很可能导致疾病状态和癌症。染色质结合蛋白BRWD3（含有Bromo结构域和WD重复蛋白3）的耗竭是已知的Cul4-DDB1 E3泛素连接酶复合物底物特异性因子，会导致H3K4me1（H3赖氨酸4位单甲基化）水平升高。然而，至今尚未明确BRWD3与H3K4甲基化之间的基本机制。在这里，我们显示耗竭BRWD3不仅会导致H3K4me1水平增加，而且会导致H3K4me3（H3赖氨酸4位三甲基化）水平降低，说明BRWD3广泛影响H3K4甲基化。通过免疫沉淀结合定量质谱法，我们确定了BRWD3与H3K4特异性赖氨酸去甲基化酶5（KDM5/Lid）之间的相互作用，这是一种从H3K4上去除三甲基和二甲基标记的酶。此外，ChIP-seq（染色体免疫沉淀测序）数据分析显示，BRWD3和KDM5在基因组中有显著的共定位，并且H3K4me3在BRWD3结合位点富集。我们显示BRWD3促进K48链聚合泛素化和KDM5的降解，而KDM5的降解依赖于BRWD3和Cul4。重要的是，耗竭KDM5完全恢复BRWD3耗竭引起的H3K4me3水平的改变，并在某种程度上恢复H3K4me1水平。综上所述，我们的结果表明BRWD3通过调节KDM5活性来平衡H3K4甲基化水平。

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 (Bromodomain and WD repeat-containing protein 3), a known substrate-specificity factor of the Cul4-DDB1 E3 ubiquitin ligase complex, results in increased H3K4me1 (H3 lysine 4 monomethylation) 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 (H3 lysine 4 trimethylation) 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 lysine demethylase 5 (KDM5/Lid), an enzyme that removes tri- and dimethyl marks from H3K4. Moreover, analysis of ChIP-seq (chromatin immunoprecipitation sequencing) data revealed that BRWD3 and KDM5 are significantly colocalized throughout the genome and 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.