Histone-modifying systems play fundamental roles in gene regulation and the development of multicellular organisms. Histone modifications that are enriched at gene regulatory elements have been heavily studied, but the function of modifications found more broadly throughout the genome remains poorly understood. This is exemplified by histone H2A monoubiquitylation (H2AK119ub1), which is enriched at Polycomb-repressed gene promoters but also covers the genome at lower levels. Here, using inducible genetic perturbations and quantitative genomics, we found that the BAP1 deubiquitylase plays an essential role in constraining H2AK119ub1 throughout the genome. Removal of BAP1 leads to pervasive genome-wide accumulation of H2AK119ub1, which causes widespread reductions in gene expression. We show that elevated H2AK119ub1 preferentially counteracts Ser5 phosphorylation on the C-terminal domain of RNA polymerase II at gene regulatory elements and causes reductions in transcription and transcription-associated histone modifications. Furthermore, failure to constrain pervasive H2AK119ub1 compromises Polycomb complex occupancy at a subset of Polycomb target genes, which leads to their derepression, providing a potential molecular rationale for why the BAP1 ortholog in Drosophila has been characterized as a Polycomb group gene. Together, these observations reveal that the transcriptional potential of the genome can be modulated by regulating the levels of a pervasive histone modification.

中文翻译：

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BAP1 限制普遍存在的 H2AK119ub1 来控制基因组的转录潜力

组蛋白修饰系统在基因调控和多细胞生物的发育中发挥着重要作用。基因调控元件富集的组蛋白修饰已被深入研究，但在整个基因组中更广泛发现的修饰功能仍知之甚少。组蛋白 H2A 单泛素化 (H2AK119ub1) 就是一个例子，它在 Polycomb 抑制的基因启动子处富集，但也覆盖了较低水平的基因组。在这里，利用诱导性遗传扰动和定量基因组学，我们发现 BAP1 去泛素化酶在限制整个基因组中的 H2AK119ub1 方面发挥着重要作用。BAP1 的去除会导致 H2AK119ub1 在全基因组范围内普遍积累，从而导致基因表达广泛减少。我们发现升高的 H2AK119ub1 优先抵消基因调控元件处 RNA 聚合酶 II C 端结构域的 Ser5 磷酸化，并导致转录和转录相关组蛋白修饰减少。此外，未能限制普遍存在的 H2AK119ub1 会损害 Polycomb 复合体对 Polycomb 靶基因子集的占据，从而导致其去抑制，这为为什么果蝇中的 BAP1 直向同源物被定性为 Polycomb 组基因提供了潜在的分子原理。总之，这些观察结果表明，基因组的转录潜力可以通过调节普遍组蛋白修饰的水平来调节。