Interdisciplinary Center for Bioinformatics (IZBI), Leipzig University, 04107 Leipzig, Germany.
Laboratory for Translational Epigenetics and Tumor Genetics, University Hospital Cologne, 50391 Cologne, Germany.
Int J Mol Sci. 2020 Mar 12;21(6):1941. doi: 10.3390/ijms21061941.
Aberrant DNA methylation in stem cells is a hallmark of aging and tumor development. Recently, we have suggested that promoter DNA hyper-methylation originates in DNA repair and that even successful DNA repair might confer this kind of epigenetic long-term change. Here, we ask for interrelations between promoter DNA methylation and histone modification changes observed in the intestine weeks after irradiation and/or following loss. We focus on H3K4me3 recruitment to the promoter of H3K27me3 target genes. By RNA- and histone ChIP-sequencing, we demonstrate that this recruitment occurs without changes of the average gene transcription and does not involve H3K9me3. Applying a mathematical model of epigenetic regulation of transcription, we show that the recruitment can be explained by stronger DNA binding of H3K4me3 and H3K27me3 histone methyl-transferases as a consequence of lower DNA methylation. This scenario implicates stable transcription despite of H3K4me3 recruitment, in agreement with our RNA-seq data. Following several kinds of stress, including moderate irradiation, stress-sensitive intestinal stem cell (ISCs) are known to become replaced by more resistant populations. Our simulation results suggest that the stress-resistant ISCs are largely protected against promoter hyper-methylation of H3K27me3 target genes.
干细胞中的异常 DNA 甲基化是衰老和肿瘤发展的一个标志。最近，我们提出启动子 DNA 超甲基化起源于 DNA 修复，即使是成功的 DNA 修复也可能导致这种表观遗传的长期变化。在这里，我们研究了辐射后数周和/或缺失后在肠道中观察到的启动子 DNA 甲基化和组蛋白修饰变化之间的相互关系。我们专注于 H3K4me3 募集到 H3K27me3 靶基因的启动子。通过 RNA 和组蛋白 ChIP-seq，我们证明这种募集发生在平均基因转录没有变化的情况下，并且不涉及 H3K9me3。应用转录的表观遗传调控的数学模型，我们表明这种募集可以通过 H3K4me3 和 H3K27me3 组蛋白甲基转移酶的更强的 DNA 结合来解释，这是由于更低的 DNA 甲基化。这种情况暗示了尽管有 H3K4me3 的募集，但仍能保持稳定的转录，这与我们的 RNA-seq 数据一致。在包括中度辐射在内的多种应激下，已知应激敏感的肠干细胞（ISCs）会被更具抗性的细胞群体所取代。我们的模拟结果表明，应激抗性 ISCs 在很大程度上受到 H3K27me3 靶基因启动子过度甲基化的保护。
