Truncation of Ube3a-ATS unsilences paternal Ube3a and ameliorates behavioral defects in the Angelman syndrome mouse model.
Truncation of Ube3a-ATS unsilences paternal Ube3a and ameliorates behavioral defects in the Angelman syndrome mouse model.
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DOI：
10.1371/journal.pgen.1004039
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Beaudet AL
中科院分区：
文献类型：
--
作者：
Meng L;Person RE;Huang W;Zhu PJ;Costa-Mattioli M;Beaudet AL
Angelman综合征（AS）是一种严重的神经发育障碍，由母亲缺乏印迹基因UBE 3A引起。患有AS的个体患有智力残疾、言语障碍和运动功能障碍。目前还没有治愈这种疾病的方法。在这里，我们评估的表型效应，激活沉默的父亲等位基因的Ube 3a的反义RNA Ube 3a-ATS在小鼠中耗尽。通过poly（A）盒插入而过早终止Ube 3a-ATS激活来自父染色体的Ube 3a的表达，并改善AS小鼠模型中的许多疾病相关症状，包括运动协调缺陷、认知缺陷和受损的长时程增强。对Ube 3a的印迹机制的研究揭示了一种双等位基因转录起始模式，其中父本Ube 3a的延伸受到抑制，这意味着正义和反义聚合酶之间的转录碰撞。这些研究证明了通过靶向Ube 3a-ATS使Ube 3a的父源拷贝非沉默作为Angelman综合征的治疗的可行性和实用性。Angelman综合征（AS）是一种在幼儿中诊断的毁灭性神经发育障碍，目前没有有效的治疗方法。其特征在于言语缺失、共济失调、智力残疾、癫痫以及频繁大笑和微笑的特征行为。该疾病是由UBE 3A的母体等位基因的丢失引起的，该等位基因由于基因组印记而优先在父亲染色体上沉默并在神经元中的母体染色体上表达。长期以来，人们一直认为，通过激活最初沉默的UBE 3A父系等位基因，可以治愈这种疾病。在本研究中，我们证明了通过基因终止其反义RNA Ube 3a-ATS的转录来激活小鼠父本Ube 3a的可行性。在AS小鼠模型中，另外从父系接受终止的Ube 3a-ATS等位基因，我们观察到Ube 3a表达的恢复，行为缺陷的改善和受损的长时程增强的逆转。我们进一步研究了Ube 3a的印迹机制，并提出了一个新的转录碰撞模型。这些结果为Ube 3a-ATS在疾病中的关键调节作用提供了坚实的体内证据，并为Angelman综合征的基因特异性治疗开辟了令人兴奋的可能性。
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by maternal deficiency of the imprinted gene UBE3A. Individuals with AS suffer from intellectual disability, speech impairment, and motor dysfunction. Currently there is no cure for the disease. Here, we evaluated the phenotypic effect of activating the silenced paternal allele of Ube3a by depleting its antisense RNA Ube3a-ATS in mice. Premature termination of Ube3a-ATS by poly(A) cassette insertion activates expression of Ube3a from the paternal chromosome, and ameliorates many disease-related symptoms in the AS mouse model, including motor coordination defects, cognitive deficit, and impaired long-term potentiation. Studies on the imprinting mechanism of Ube3a revealed a pattern of biallelic transcription initiation with suppressed elongation of paternal Ube3a, implicating transcriptional collision between sense and antisense polymerases. These studies demonstrate the feasibility and utility of unsilencing the paternal copy of Ube3a via targeting Ube3a-ATS as a treatment for Angelman syndrome. Angelman syndrome (AS) is a devastating neurodevelopmental disorder diagnosed in young children, currently with no effective treatments. It is characterized by absence of speech, ataxia, intellectual disability, epilepsy, and a characteristic behavior of frequent laughter and smiling. The disease is caused by loss of the maternal allele of UBE3A, which is preferentially silenced on the paternal chromosome and expressed on the maternal chromosome in neurons due to genomic imprinting. It has been long proposed that by activating the originally silenced paternal allele of UBE3A, the disease may be cured. Here in our research, we demonstrated the feasibility of activating paternal Ube3a in mice by terminating the transcription of its antisense RNA Ube3a-ATS genetically. In the AS mouse model who additionally receives the terminated Ube3a-ATS allele from the paternal side, we observed restoration of Ube3a expression, amelioration of behavioral defects and reversal of the impaired long-term potentiation. We further studied the imprinting mechanisms of Ube3a and proposed a novel transcriptional collision model. These results provide solid in vivo evidence for a key regulatory role of Ube3a-ATS in the disease and open up an exciting possibility of a gene-specific treatment for Angelman syndrome.
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