Nature biotechnology：新发现染色质绝缘子或可用于人类基因治疗

               

2015年2月2日讯 /生物谷BIOON/ –插入突变和遗传毒性通常代表造血系统肿瘤的恶化，同时也是实现基因治疗前景所面临的最大障碍。George Stamatoyannopoulos等人研究出一种能够识别作为绝缘子发挥功能的紧凑序列元件的方法，或对实现基因治疗的美好前景提供重要推动作用。最近这一研究成果在线发表在国际生物学期刊nature biotechnology上。

 

绝缘子是一种能够阻断增强子与细胞癌基因调控元件相互作用的序列元件。虽然绝缘子能够阻断增强子的促转录功能，但至今没有发现人类基因组中具有高抑制潜能的绝缘子。Mingdong Liu等人通过研究发现一种能够识别绝缘子的方法，他们发现这些绝缘子元件被绝缘子蛋白CTCF高度占据，并且这些元件都具有很高的DNase I敏感性，但这些序列只代表人类基因组中CTCF识别序列的一小部分。研究人员表示，这些被识别为绝缘子的基因元件能够发挥阻断增强子活性的作用，并通过肿瘤易感动物模型证实这些绝缘子元件能够降低肿瘤发生率。研究人员发现的这些绝缘子能够被病毒载体有效容纳，并且对病毒滴度没有不利影响。

 

综上所述，该文章发现了鉴定人类基因组中绝缘子的有效方法，并且通过实验证明这些绝缘子元件能够有效阻断增强子活性，抑制肿瘤发生。这项研究成果或应用基因治疗的方法治疗遗传疾病提供重要启示。（生物谷Bioon.com）

 

 

 

 

Genomic discovery of potent chromatin insulators for human gene therapy

 

Mingdong Liu, Matthew T Maurano, Hao Wang, Heyuan Qi, Chao-Zhong Song, Patrick A Navas, David W Emery, John A Stamatoyannopoulos & George Stamatoyannopoulos

 

Insertional mutagenesis and genotoxicity, which usually manifest as hematopoietic malignancy, represent major barriers to realizing the promise of gene therapy. Although insulator sequences that block transcriptional enhancers could mitigate or eliminate these risks, so far no human insulators with high functional potency have been identified. Here we describe a genomic approach for the identification of compact sequence elements that function as insulators. These elements are highly occupied by the insulator protein CTCF, are DNase I hypersensitive and represent only a small minority of the CTCF recognition sequences in the human genome. We show that the elements identified acted as potent enhancer blockers and substantially decreased the risk of tumor formation in a cancer-prone animal model. The elements are small, can be efficiently accommodated by viral vectors and have no detrimental effects on viral titers. The insulators we describe here are expected to increase the safety of gene therapy for genetic diseases.