JADE is a core subunit of the HBO1 acetyltransferase complex that regulates developmental and epigenetic programs and promotes gene transcription. Here we describe the mechanism by which JADE facilitates recruitment of the HBO1 complex to chromatin and mediates its enzymatic activity. Structural, genomic and complex assembly in vivo studies show that the PZP (PHD1–zinc-knuckle–PHD2) domain of JADE engages the nucleosome through binding to histone H3 and DNA and is necessary for the association with chromatin targets. Recognition of unmethylated H3K4 by PZP directs enzymatic activity of the complex toward histone H4 acetylation, whereas H3K4 hypermethylation alters histone substrate selectivity. We demonstrate that PZP contributes to leukemogenesis, augmenting transforming activity of the NUP98–JADE2 fusion. Our findings highlight biological consequences and the impact of the intact JADE subunit on genomic recruitment, enzymatic function and pathological activity of the HBO1 complex.

JADE 是 HBO1 乙酰转移酶复合物的核心亚基，调节发育和表观遗传程序并促进基因转录。在这里，我们描述了 JADE 促进 HBO1 复合物募集到染色质并介导其酶活性的机制。体内结构、基因组和复杂组装研究表明，JADE 的 PZP (PHD1-zinc-knuckle-PHD2) 结构域通过与组蛋白 H3 和 DNA 结合而与核小体结合，对于与染色质靶标的关联是必需的。PZP 对未甲基化 H3K4 的识别将复合物的酶活性导向组蛋白 H4 乙酰化，而 H3K4 高甲基化会改变组蛋白底物选择性。我们证明 PZP 有助于白血病发生，增强 NUP98-JADE2 融合体的转化活性。我们的研究结果强调了完整的 JADE 亚基对 HBO1 复合物的基因组募集、酶功能和病理活性的生物学后果和影响。