Abstract：
Regulation of histone acetylation dictates patterns of gene expression and hence cell identity. Due to their clinical relevance in cancer biology, understanding how human embryonic stem cells (hESCs) regulate their genomic patterns of histone acetylation is critical, but it remains largely to be investigated. Here, we provide evidence that acetylation of histone H3 lysine-18 (H3K18ac) and lysine-27 (H3K27ac) is only partially established by p300 in stem cells, while it represents the main histone acetyltransferase (HAT) for these marks in somatic cells. Our analysis reveals that whereas p300 marginally associated with H3K18ac and H3K27ac in hESCs, it largely overlapped with these histone marks upon differentiation. Interestingly, we show that H3K18ac is found at \"stemness\" genes enriched in RNA polymerase III transcription factor C (TFIIIC) in hESCs, whilst lacking p300. Moreover, TFIIIC was also found in the vicinity of genes involved in neuronal biology, although devoid of H3K18ac. Our data suggest a more complex pattern of HATs responsible for histone acetylations in hESCs than previously considered, suggesting a putative role for H3K18ac and TFIIIC in regulating \"stemness\" genes as well as genes associated with neuronal differentiation of hESCs. The results break ground for possible new paradigms for genome acetylation in hESCs that could lead to new avenues for therapeutic intervention in cancer and developmental diseases.
摘要：
组蛋白乙酰化的调节决定了基因表达的模式，从而决定了细胞的同一性。由于它们在癌症生物学中的临床相关性，了解人类胚胎干细胞（hESCs）如何调节其组蛋白乙酰化的基因组模式至关重要，但在很大程度上仍有待调查。这里,我们提供的证据表明，组蛋白H3赖氨酸-18（H3K18ac）和赖氨酸-27（H3K27ac）的乙酰化仅部分通过p300在干细胞中建立，而它代表了体细胞中这些标记的主要组蛋白乙酰转移酶（HAT）。我们的分析表明，尽管p300在hESC中与H3K18ac和H3K27ac略有相关，它在分化时与这些组蛋白标记大部分重叠。有趣的是,我们显示H3K18ac在hESCs中的RNA聚合酶III转录因子C（TFIIIC）富集的“干性”基因中发现，缺少P300此外，在涉及神经元生物学的基因附近也发现了TFIIC，虽然没有H3K18ac。我们的数据表明，与以前认为的相比，在hESC中负责组蛋白乙酰化的HAT模式更为复杂，提示H3K18ac和TFIIIC在调节“干性”基因以及与hESCs神经元分化相关的基因中的推定作用。结果为hESC基因组乙酰化的可能新范例开辟了基础，这可能导致癌症和发育疾病的治疗干预的新途径。
