Alternative splicing (AS) and alternative polyadenylation (APA) generate diverse transcripts in mammalian genomes during development and differentiation. Epigenetic marks such as trimethylation of histone H3 lysine 36 (H3K36me3) and DNA methylation play a role in generating transcriptome diversity. Intragenic CpG islands (iCGIs) and their corresponding host genes exhibit dynamic epigenetic and gene expression patterns during development and between different tissues. We hypothesise that iCGI-associated H3K36me3, DNA methylation and transcription can influence host gene AS and/or APA. We investigate H3K36me3 and find that this histone mark is not a major regulator of AS or APA in our model system. Genomewide, we identify over 4000 host genes that harbour an iCGI in the mammalian genome, including both previously annotated and novel iCGI/host gene pairs. The transcriptional activity of these iCGIs is tissue- and developmental stage-specific and, for the first time, we demonstrate that the premature termination of host gene transcripts upstream of iCGIs is closely correlated with the level of iCGI transcription in a DNA-methylation independent manner. These studies suggest that iCGI transcription, rather than H3K36me3 or DNA methylation, interfere with host gene transcription and pre-mRNA processing genomewide and contributes to the spatiotemporal diversification of both the transcriptome and proteome.

中文翻译：

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基因内 CpG 岛的转录影响时空宿主基因前 mRNA 加工。

选择性剪接（AS）和选择性多腺苷酸化（APA）在发育和分化过程中在哺乳动物基因组中产生不同的转录本。组蛋白 H3 赖氨酸 36 (H3K36me3) 的三甲基化和 DNA 甲基化等表观遗传标记在转录组多样性的产生中发挥着重要作用。基因内 CpG 岛 (iCGI) 及其相应的宿主基因在发育过程中和不同组织之间表现出动态的表观遗传和基因表达模式。我们假设 iCGI 相关的 H3K36me3、DNA 甲基化和转录可以影响宿主基因 AS 和/或 APA。我们研究了 H3K36me3，发现该组蛋白标记并不是我们模型系统中 AS 或 APA 的主要调节因子。在全基因组范围内，我们在哺乳动物基因组中鉴定了 4000 多个含有 iCGI 的宿主基因，包括先前注释的和新的 iCGI/宿主基因对。这些 iCGI 的转录活性具有组织和发育阶段特异性，并且我们首次证明 iCGI 上游宿主基因转录物的过早终止与 iCGI 转录水平以 DNA 甲基化无关的方式密切相关。这些研究表明，iCGI 转录（而不是 H3K36me3 或 DNA 甲基化）在全基因组范围内干扰宿主基因转录和前 mRNA 处理，并有助于转录组和蛋白质组的时空多样化。