Butyrate Induced IGF2 Activation Correlated with Distinct Chromatin Signatures Due to Histone Modification.
Butyrate Induced IGF2 Activation Correlated with Distinct Chromatin Signatures Due to Histone Modification.
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DOI：
10.4137/grsb.s11243
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Li CJ
中科院分区：
文献类型：
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作者：
Shin JH;Li RW;Gao Y;Bickhart DM;Liu GE;Li W;Wu S;Li CJ
组蛋白修饰已成为调节基因组转录状态的一种非常重要的机制。胰岛素样生长因子2（IGF 2）是一种肽类激素，控制各种细胞过程，包括增殖和凋亡。H19基因与IGF 2基因紧密连锁，IGF 2和H19是受调控的印迹基因。父本等位基因上H19启动子的表观遗传标记（超甲基化）在允许IGF 2的父本等位基因表达中起着至关重要的作用。我们以前的研究表明丁酸调节IGF 2的表达以及编码IGF结合蛋白的基因。为了进一步了解组蛋白修饰及其在控制IGF 2/H19基因表达中的调控潜力，我们采用RNA-seq结合Chip-seq技术研究了与牛细胞IGF 2/H19基因表达相关的一些关键组蛋白的组蛋白修饰状态。构建了丁酸盐诱导的IGF 2/H19位点主要染色质修饰的高分辨率图谱，以说明染色质修饰景观的基本关联，其可能在IGF 2基因的激活中发挥作用。高清晰度表观基因组图谱显示，IGF 2和H19在其编码区和启动子区具有不同的染色质修饰模式，如TSS和TTS。此外，IGF 2/H19基因座的差异甲基化区域（DMR）与组蛋白修饰（乙酰化和甲基化）之间的相关性表明，DNA甲基化、组蛋白甲基化和组蛋白乙酰化的表观遗传特征/标记在表达的IGF 2和沉默的H19基因上差异分布。丁酸诱导的H19上游调控域组蛋白乙酰化状态的区域性改变可能与H19表达减少和IGF 2的强烈激活有关。我们的研究结果提供了深入了解丁酸酯诱导的IGF 2印迹（LOI）的损失和组蛋白修饰的基因表达调控的机制。
Histone modification has emerged as a very important mechanism regulating the transcriptional status of the genome. Insulin-like growth factor 2 (IGF2) is a peptide hormone controlling various cellular processes, including proliferation and apoptosis. H19 gene is closely linked to IGF2 gene, and IGF2 and H19 are reciprocally regulated imprinted genes. The epigenetic signature of H19 promoter (hypermethylation) on the paternal allele plays a vital role in allowing the expression of the paternal allele of IGF2. Our previous studies demonstrate that butyrate regulates the expression of IGF2 as well as genes encoding IGF Binding proteins. To obtain further understanding of histone modification and its regulatory potentials in controlling IGF2/H19 gene expression, we investigated the histone modification status of some key histones associated with the expression of IGF2/H19 genes in bovine cells using RNA-seq in combination with Chip-seq technology. A high-resolution map of the major chromatin modification at the IGF2/H19 locus induced by butyrate was constructed to illustrate the fundamental association of the chromatin modification landscape that may play a role in the activation of the IGF2 gene. High-definition epigenomic landscape mapping revealed that IGF2 and H19 have distinct chromatin modification patterns at their coding and promoter regions, such as TSSs and TTSs. Moreover, the correlation between the differentially methylated regions (DMRs) of IGF2/H19 locus and histone modification (acetylation and methylation) indicated that epigenetic signatures/markers of DNA methylation, histone methylation and histone acetylation were differentially distributed on the expressed IGF2 and silenced H19 genes. Our evidence also suggests that butyrate-induced regional changes of histone acetylation statusin the upstream regulation domain of H19 may be related to the reduced expression of H19 and strong activation of IGF2. Our results provided insights into the mechanism of butyrate-induced loss of imprinting (LOI) of IGF2 and regulation of gene expression by histone modification.