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首页> 外文期刊>Journal of cellular biochemistry. >Inhibition of histone acetyltransferase by glycosaminoglycans.
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Inhibition of histone acetyltransferase by glycosaminoglycans.

机译：糖胺聚糖对组蛋白乙酰转移酶的抑制作用。

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摘要

Histone acetyltransferases (HATs) are a class of enzymes that participate in modulating chromatin structure and gene expression. Altered HAT activity has been implicated in a number of diseases, yet little is known about the regulation of HATs. In this study, we report that glycosaminoglycans (GAGs) are potent inhibitors of p300 and pCAF HAT activities in vitro, with heparin and heparan sulfate proteoglycans (HSPGs) being the most potent inhibitors. The mechanism of inhibition by heparin was investigated. The ability of heparin to inhibit HAT activity was in part dependent upon its size and structure, as small heparin-derived oligosaccharides (>8 sugars) and N-desulfated or O-desulfated heparin showed reduced inhibitory activity. Heparin was shown to bind to pCAF; and enzyme assays indicated that heparin shows the characteristics of a competitive-like inhibitor causing an approximately 50-fold increase in the apparent Km of pCAF for histone H4. HSPGs isolated from corneal and pulmonary fibroblasts inhibited HAT activity with similar effectiveness as heparin. As evidence that endogenous GAGs might be involved in modulating histone acetylation, the direct addition of heparin to pulmonary fibroblasts resulted in an approximately 50% reduction of histone H3 acetylation after 6 h of treatment. In addition, Chinese hamster ovary cells deficient in GAG synthesis showed increased levels of acetylated histone H3 compared to wild-type parent cells. GAGs represent a new class of HAT inhibitors that might participate in modulating cell function by regulating histone acetylation.
机译：组蛋白乙酰基转移酶（HATs）是一类参与调节染色质结构和基因表达的酶。改变的HAT活性与多种疾病有关，但对HAT的调控知之甚少。在这项研究中，我们报道糖胺聚糖（GAGs）是体外p300和pCAF HAT活性的有效抑制剂，其中肝素和硫酸乙酰肝素蛋白聚糖（HSPGs）是最有效的抑制剂。研究了肝素抑制作用的机理。肝素抑制HAT活性的能力部分取决于其大小和结构，因为小肝素衍生的低聚糖（> 8个糖）和N-脱硫或O-脱硫肝素显示出降低的抑制活性。肝素被证明与pCAF结合。酶分析表明，肝素具有竞争性抑制剂的特性，可导致组蛋白H4的pCAF表观Km值增加约50倍。从角膜和肺成纤维细胞中分离出的HSPG抑制HAT的活性与肝素相似。作为内源性GAG可能参与调节组蛋白乙酰化的证据，治疗6小时后，将肝素直接添加到肺成纤维细胞中导致组蛋白H3乙酰化减少约50％。此外，与野生型亲本细胞相比，GAG合成缺陷的中国仓鼠卵巢细胞显示乙酰化组蛋白H3的水平增加。 GAGs代表一类新的HAT抑制剂，可能通过调节组蛋白乙酰化参与调节细胞功能。

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