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首页> 外文期刊>Epigenetics & Chromatin >Allele-specific transcriptional elongation regulates monoallelic expression of the IGF2BP1 gene
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Allele-specific transcriptional elongation regulates monoallelic expression of the IGF2BP1 gene

机译：等位基因特异性转录延伸调控IGF2BP1基因的单等位基因表达

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Background Random monoallelic expression contributes to phenotypic variation of cells and organisms. However, the epigenetic mechanisms by which individual alleles are randomly selected for expression are not known. Taking cues from chromatin signatures at imprinted gene loci such as the insulin-like growth factor 2 gene 2 (IGF2), we evaluated the contribution of CTCF, a zinc finger protein required for parent-of-origin-specific expression of the IGF2 gene, as well as a role for allele-specific association with DNA methylation, histone modification and RNA polymerase II. Results Using array-based chromatin immunoprecipitation, we identified 293 genomic loci that are associated with both CTCF and histone H3 trimethylated at lysine 9 (H3K9me3). A comparison of their genomic positions with those of previously published monoallelically expressed genes revealed no significant overlap between allele-specifically expressed genes and colocalized CTCF/H3K9me3. To analyze the contributions of CTCF and H3K9me3 to gene regulation in more detail, we focused on the monoallelically expressed IGF2BP1 gene. In vitro binding assays using the CTCF target motif at the IGF2BP1 gene, as well as allele-specific analysis of cytosine methylation and CTCF binding, revealed that CTCF does not regulate mono- or biallelic IGF2BP1 expression. Surprisingly, we found that RNA polymerase II is detected on both the maternal and paternal alleles in B lymphoblasts that express IGF2BP1 primarily from one allele. Thus, allele-specific control of RNA polymerase II elongation regulates the allelic bias of IGF2BP1 gene expression. Conclusions Colocalization of CTCF and H3K9me3 does not represent a reliable chromatin signature indicative of monoallelic expression. Moreover, association of individual alleles with both active (H3K4me3) and silent (H3K27me3) chromatin modifications (allelic bivalent chromatin) or with RNA polymerase II also fails to identify monoallelically expressed gene loci. The selection of individual alleles for expression occurs in part during transcription elongation.
机译：背景技术随机单等位基因表达有助于细胞和生物的表型变异。但是，尚不清楚通过随机选择单个等位基因进行表达的表观遗传机制。从印记基因位点（如胰岛素样生长因子2基因2（IGF2））的染色质特征中获取线索，我们评估了CTCF的贡献，CTCF是IGF2基因的母体特异性表达所必需的锌指蛋白，以及等位基因特异性结合与DNA甲基化，组蛋白修饰和RNA聚合酶II的作用。结果使用基于阵列的染色质免疫沉淀，我们确定了293个基因组位点，它们与CTCF和在赖氨酸9（H3K9me3）处三甲基化的组蛋白H3相关。将它们的基因组位置与先前发表的单等位基因表达的基因组位置进行比较后，发现等位基因特异性表达的基因与共定位的CTCF / H3K9me3之间没有明显的重叠。为了更详细地分析CTCF和H3K9me3对基因调控的贡献，我们集中于单等位表达的IGF2BP1基因。使用IGF2BP1基因上的CTCF靶基序进行的体外结合测定以及胞嘧啶甲基化和CTCF结合的等位基因特异性分析显示，CTCF不调节单等位基因或双等位基因IGF2BP1的表达。令人惊讶地，我们发现在主要从一个等位基因表达IGF2BP1的B淋巴母细胞的母本和父本等位基因上均检测到RNA聚合酶II。因此，RNA聚合酶II延伸的等位基因特异性控制可调节IGF2BP1基因表达的等位基因偏倚。结论CTCF和H3K9me3的共定位不能代表表明单等位基因表达的可靠的染色质特征。此外，单个等位基因与活性（H3K4me3）和沉默（H3K27me3）染色质修饰（等位基因二价染色质）或RNA聚合酶II的关联也无法鉴定单等位基因表达的基因位点。用于表达的个体等位基因的选择部分在转录延伸期间发生。

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