Regulation of the large (∼1000 kb) imprinted murine Ube3a antisense transcript by alternative exons upstream of Snurf/Snrpn
Regulation of the large (∼1000 kb) imprinted murine Ube3a antisense transcript by alternative exons upstream of Snurf/Snrpn
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DOI：
10.1093/nar/gkh670
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发表时间：
2004-06-01
影响因子：
14.9
通讯作者：
Lalande, M
中科院分区：
文献类型：
--
作者：
Landers, M;Bancescu, DL;Lalande, M
大多数Angelman综合征（AS）病例是由于泛素蛋白连接酶3A（UBE 3A）的缺失或失活所致，UBE 3A是一种在脑中显示母体特异性表达的基因。父亲UBE 3A等位基因在脑中的表观遗传沉默似乎是由非编码UBE 3A反义（UBE 3A-ATS）介导的。在人类中，UBE 3A-ATS与UBE 3A相似，从含有顺式作用印记中心（IC）的小核核糖核蛋白N（SNURF/SNRPN）启动子区延伸450 kb。单个大反义转录物的概念很难与SNURF/SNRPN显示普遍存在的表达模式的观察相一致，而与UBE 3A重叠的UBE 3A-ATS的更远端部分是脑特异性的。为了解决这个问题，我们研究了从几个可选的外显子分散在一个500 kb的区域上游的Snurf/Snrpn的小鼠转录本。类似于Ube 3a-ATS，这些上游（U）含外显子的转录物在神经发生的细胞培养模型中的神经元分化阶段表达。这些发现表明了新的假设，即Ube 3a-ATS的脑特异性转录受U外显子而不是Snurf/Snrpn外显子1的调节，如先前从人类研究中所提出的。为了支持这一假设，我们描述了U-Ube 3a-ATS转录本，其中U外显子被剪接到Ube 3a-ATS上，排除了Snurf-Snrpn。我们还表明，鼠U外显子出现的基因组复制的片段，包括IC的元素，这表明脑特异性沉默Ube 3a是由于多个选择性剪接IC-Ube 3a-ATS转录。
Most cases of Angelman syndrome (AS) result from loss or inactivation of ubiquitin protein ligase 3A (UBE3A), a gene displaying maternal-specific expression in brain. Epigenetic silencing of the paternal UBE3A allele in brain appears to be mediated by a non-coding UBE3A antisense (UBE3A-ATS). In human, UBE3A-ATS extends similar to450 kb to UBE3A from the small nuclear ribonucleoprotein N (SNURF/SNRPN) promoter region that contains a cis-acting imprinting center (IC). The concept of a single large antisense transcript is difficult to reconcile with the observation that SNURF/SNRPN shows a ubiquitous pattern of expression while the more distal part of UBE3A-ATS, which overlaps UBE3A, is brain specific. To address this problem, we examined murine transcripts initiating from several alternative exons dispersed within a 500 kb region upstream of Snurf/Snrpn. Similar to Ube3a-ATS, these upstream (U) exon-containing transcripts are expressed at neuronal stages of differentiation in a cell culture model of neurogenesis. These findings suggest the novel hypothesis that brain-specific transcription of Ube3a-ATS is regulated by the U exons rather than Snurf/Snrpn exon 1 as previously suggested from human studies. In support of this hypothesis, we describe U-Ube3a-ATS transcripts where U exons are spliced to Ube3a-ATS with the exclusion of Snurf-Snrpn. We also show that the murine U exons have arisen by genomic duplication of segments that include elements of the IC, suggesting that the brain specific silencing of Ube3a is due to multiple alternatively spliced IC-Ube3a-ATS transcripts.