Methylation of histone H3 at lysine 36 (H3K36me3) marks active chromatin. The mark is interpreted by epigenetic readers that assist transcription and safeguard the integrity of the chromatin fiber. The chromodomain protein MSL3 binds H3K36me3 to target X-chromosomal genes in male Drosophila for dosage compensation. The PWWP-domain protein JASPer recruits the JIL1 kinase to active chromatin on all chromosomes. Unexpectedly, depletion of K36me3 had variable, locus-specific effects on the interactions of those readers. This observation motivated a systematic and comprehensive study of K36 methylation in a defined cellular model. Contrasting prevailing models, we found that K36me1, K36me2 and K36me3 each contribute to distinct chromatin states. A gene-centric view of the changing K36 methylation landscape upon depletion of the three methyltransferases Set2, NSD and Ash1 revealed local, context-specific methylation signatures. Set2 catalyzes K36me3 predominantly at transcriptionally active euchromatin. NSD places K36me2/3 at defined loci within pericentric heterochromatin and on weakly transcribed euchromatic genes. Ash1 deposits K36me1 at regions with enhancer signatures. The genome-wide mapping of MSL3 and JASPer suggested that they bind K36me2 in addition to K36me3, which was confirmed by direct affinity measurement. This dual specificity attracts the readers to a broader range of chromosomal locations and increases the robustness of their actions.

中文翻译：

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三种果蝇甲基转移酶的基因组背景依赖性组蛋白 H3K36 甲基化及其对专用染色质读取器的影响


组蛋白 H3 在赖氨酸 36 (H3K36me3) 处的甲基化标志着活性染色质。该标记由表观遗传阅读器解释，帮助转录并保护染色质纤维的完整性。染色质结构域蛋白 MSL3 将 H3K36me3 结合到雄性果蝇的 X 染色体基因上，以实现剂量补偿。 PWWP 结构域蛋白 JASPer 招募 JIL1 激酶来激活所有染色体上的染色质。出乎意料的是，K36me3 的耗尽对这些读者的相互作用产生了可变的、基因座特异性的影响。这一观察结果激发了对特定细胞模型中 K36 甲基化的系统和全面研究。对比主流模型，我们发现 K36me1、K36me2 和 K36me3 各自对不同的染色质状态有贡献。以基因为中心观察三种甲基转移酶 Set2、NSD 和 Ash1 耗尽后 K36 甲基化景观的变化，揭示了局部的、特定于环境的甲基化特征。 Set2 主要催化具有转录活性的常染色质的 K36me3。 NSD 将 K36me2/3 置于中心异染色质内的指定位点和弱转录的常染色质基因上。 Ash1 将 K36me1 沉积在具有增强子签名的区域。 MSL3 和 JASPer 的全基因组图谱表明，除了 K36me3 之外，它们还结合 K36me2，这一点通过直接亲和力测量得到证实。这种双重特异性将读者吸引到更广泛的染色体位置，并增加了他们的行动的稳健性。