Bidirectional imprinting of a single gene:: GNAS1 encodes maternally, paternally, and biallelically derived proteins
Bidirectional imprinting of a single gene:: GNAS1 encodes maternally, paternally, and biallelically derived proteins
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DOI：
10.1073/pnas.95.26.15475
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发表时间：
1998-12-22
影响因子：
11.1
通讯作者：
Bonthron, DT
中科院分区：
文献类型：
--
作者：
Hayward, BE;Moran, V;Bonthron, DT
GNAS1基因编码鸟嘌呤核苷酸结合蛋白G（S）的α亚基，该蛋白G（S）将其通过肽激素受体信号传导至cAMP的产生。 GNAS1突变是激素抗性综合征假甲状腺功能减退症IA型（PHP-IA）的基础，因此PHP-IA所显示的母体遗传引起了人们对GNAS1印记的怀疑。尽管有这一建议，在大多数组织中，g（s）alpha是双重编码的。相比之下，也是由GNAS1编码的大G蛋白XLαS是含父衍生的。由于PHP-IA的遗传预测了母体而不是含天式的转录本的存在，因此我们研究了来自GNAS1的其他mRNA的等位基因起源。我们发现该基因在其等位基因特异性调节的复杂性中是显着的。两个上游启动子，每个启动子与大型编码外显子相关，仅为11 kb，但显示出等位基因特异性甲基化和单相关转录的相反模式。这些外显子中的5'越多地编码神经内分泌分泌蛋白Nesp55，该蛋白仅根据母体等位基因表达。 Nesp55外显子是paternally表达的XL alpha s外显子的11 kb 5'。来自这两个启动子的转录本均分离到GNAS1外显子2上，但没有共享编码序列。尽管它们的结构不相关，但具有相反等位基因起源的编码蛋白都与神经内分泌组织的调节分泌有关。值得注意的是，母体（NESP55），Paternally（XL alpha s）和双乳脂（G（S）alpha）衍生的蛋白质都是由不同的启动子使用和GNAS1的替代剪接而产生的，GNAS1的替代剪接是一种基因，在父亲和父亲和同时表现出了同时存在着印记的基因产妇的方向。
The GNAS1 gene encodes the alpha subunit of the guanine nucleotide-binding protein G(S), which couples signaling through peptide hormone receptors to cAMP generation. GNAS1 mutations underlie the hormone resistance syndrome pseudohypoparathyroidism type Ia (PHP-Ia), so the maternal inheritance displayed by PHP-Ia has raised suspicions that GNAS1 is imprinted. Despite this suggestion, in most tissues G(S)alpha is biallelically encoded. In contrast, the large G protein XL alpha s, also encoded by GNAS1, is paternally derived. Because the inheritance of PHP-Ia predicts the existence of maternally, rather than paternally, expressed transcripts, we have investigated the allelic origin of other mRNAs derived from GNAS1. We find this gene to be remarkable in the complexity of its allele-specific regulation. Two upstream promoters, each associated with a large coding exon, lie only 11 kb apart, yet show opposite patterns of allele-specific methylation and monoallelic transcription. The more 5' of these exons encodes the neuroendocrine secretory protein NESP55, which is expressed exclusively from the maternal allele. The NESP55 exon is 11 kb 5' to the paternally expressed XL alpha s exon. The transcripts from these two promoters both splice onto GNAS1 exon 2, yet share no coding sequences. Despite their structural unrelatedness, the encoded proteins, of opposite allelic origin, both have been implicated in regulated secretion in neuroendocrine tissues. Remarkably, maternally (NESP55), paternally (XL alpha s), and biallelically (G(S)alpha) derived proteins all are produced by different patterns of promoter use and alternative splicing of GNAS1, a gene showing simultaneous imprinting in both the paternal and maternal directions.