Gurdon Institute and Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
PLoS One. 2012;7(1):e29765. doi: 10.1371/journal.pone.0029765. Epub 2012 Jan 3.
Post-translational modification of histone proteins are known to play an important role in regulating chromatin structure. In an effort to find additional histone modifications we set out to screen enzymes of the 2-oxoglutarate and Fe(II)-dependent (2-OG-Fe(II)) dioxygenase family for activity towards histones. Here we show that the Schizosaccharomyces pombe 2-OG-Fe(II) dioxygenase domain containing protein-2 (Ofd2) is a histone H2A dioxygenase enzyme. Using a combination of peptide screening and alanine scanning substitution analysis, we identify an HxxLR motif in H2A as a substrate for Ofd2 activity. Transcriptional profiling indicates that Ofd2 regulates the repression of oxidative phosphorylation genes during hypoxic stress. We show that Ofd2 is recruited to the 5' end of oxidative phosphorylation genes specifically during hypoxia and that it uses its dioxygenase activity to regulate their transcription. Together, these data uncover a novel histone H2A modifying activity involved in the regulation of gene expression during hypoxia.
组蛋白蛋白的翻译后修饰被认为在调节染色质结构中起着重要作用。为了寻找其他组蛋白修饰，我们着手筛选 2-氧戊二酸和 Fe(II)依赖性（2-OG-Fe(II)）双加氧酶家族的酶对组蛋白的活性。在这里，我们表明裂殖酵母 2-OG-Fe(II)双加氧酶结构域包含蛋白-2（Ofd2）是一种组蛋白 H2A 双加氧酶酶。通过肽筛选和丙氨酸扫描取代分析的组合，我们在 H2A 中鉴定出一个 HxxLR 基序作为 Ofd2 活性的底物。转录谱分析表明，Ofd2 在低氧应激期间调节氧化磷酸化基因的抑制。我们表明，Ofd2 在低氧条件下特异性地被募集到氧化磷酸化基因的 5'端，并且它利用其双加氧酶活性来调节它们的转录。总之，这些数据揭示了一种涉及低氧条件下基因表达调控的新型组蛋白 H2A 修饰活性。
