EPIGENETIC MECHANISMS UNDERLYING THE IMPRINTING OF THE MOUSE H19-GENE
EPIGENETIC MECHANISMS UNDERLYING THE IMPRINTING OF THE MOUSE H19-GENE
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DOI：
10.1101/gad.7.9.1663
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发表时间：
1993-09-01
影响因子：
10.5
通讯作者：
TILGHMAN, SM
中科院分区：
文献类型：
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作者：
BARTOLOMEI, MS;WEBBER, AL;TILGHMAN, SM
在哺乳动物中，H19基因的表达受亲本印记控制。H19是一种不寻常的基因，编码一种功能未知的RNA，仅在母体染色体上表达。在小鼠中，其位于Igf2基因下游90 kb处，Igf2基因编码胎儿特异性生长因子胰岛素样生长因子II，并且主要从父系遗传的染色体表达。在这份报告中，我们已经利用种间杂交小鼠，以确定男性特异性DNA甲基化的7至9 kb的结构域周围的H19基因及其启动子。这种等位基因特异性甲基化可以作为抑制H19父系等位基因转录的标记。与该提议一致，H19启动子仅在相对未甲基化的活性母体等位基因上显示开放的染色质构象。相反，位于甲基化结构域之外的细胞类型特异性增强子对母体和父体染色体上的细胞核中的限制性内切酶消化高度敏感。等位基因特异性甲基化结构域，耦合到两个H19增强子，包含所有必要的信息，其印记进行了测试，通过检查两个转基因株系含有一个内部删除的H19转基因。两者都显示了转基因的父系特异性甲基化和母系特异性表达。虽然这两种品系都没有在近交遗传背景下进行过测试，因此不能正式排除复合修饰剂的作用，但结果表明已经鉴定了H19印迹所需的序列。
The expression of the H19 gene is governed by parental imprinting in mammals. H19, an unusual gene encoding an RNA with no known function, is exclusively expressed from the maternal chromosome. In mouse, it lies 90 kb downstream from the Igf2 gene, which encodes a fetal-specific growth factor, insulin-like growth factor II, and is expressed primarily from the paternally inherited chromosome. In this report we have utilized interspecific hybrid mice to identify male-specific DNA methylation of a 7- to 9-kb domain surrounding the H19 gene and its promoter. This allele-specific methylation could function as a mark to suppress transcription of the H19 paternal allele. Consistent with this proposal, the H19 promoter displayed an open chromatin conformation only on the relatively unmethylated active maternal allele. In contrast, a cell type-specific enhancer that lies outside the methylation domain is hypersensitive to restriction enzyme digestion in nuclei on both maternal and paternal chromosomes. That the allele-specific methylation domain, coupled to the two H19 enhancers, contains all the information necessary for its imprinting was tested by examining two transgenic lines containing an internally deleted H19 transgene. Both displayed paternal-specific methylation of the transgene and maternal-specific expression. Although neither line has been tested in an inbred genetic background, and therefore the action of complex modifiers cannot be formally excluded, the result suggests that the sequences necessary for the imprinting of H19 have been identified.