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首页> 外文期刊>BMC Genomics >Genome-wide map of quantified epigenetic changes during in vitro chondrogenic differentiation of primary human mesenchymal stem cells
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Genome-wide map of quantified epigenetic changes during in vitro chondrogenic differentiation of primary human mesenchymal stem cells

机译：全基因组图谱的人类原代间充质干细胞体外软骨分化过程中的表观遗传学变化

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Background For safe clinical application of engineered cartilage made from mesenchymal stem cells (MSCs), molecular mechanisms for chondrogenic differentiation must be known in detail. Changes in gene expression and extracellular matrix synthesis have been extensively studied, but the epigenomic modifications underlying these changes have not been described. To this end we performed whole-genome chromatin immunoprecipitation and deep sequencing to quantify six histone modifications, reduced representation bisulphite sequencing to quantify DNA methylation and mRNA microarrays to quantify gene expression before and after 7?days of chondrogenic differentiation of MSCs in an alginate scaffold. To add to the clinical relevance of our observations, the study is based on primary bone marrow-derived MSCs from four donors, allowing us to investigate inter-individual variations. Results We see two levels of relationship between epigenetic marking and gene expression. First, a large number of genes ontogenetically linked to MSC properties and the musculoskeletal system are epigenetically prepatterned by moderate changes in H3K4me3 and H3K9ac near transcription start sites. Most of these genes remain transcriptionally unaltered. Second, transcriptionally upregulated genes, more closely associated with chondrogenesis, are marked by H3K36me3 in gene bodies, highly increased H3K4me3 and H3K9ac on promoters and 5' end of genes, and increased H3K27ac and H3K4me1 marking in at least one enhancer region per upregulated gene. Within the 7-day time frame, changes in promoter DNA methylation do not correlate significantly with changes in gene expression. Inter-donor variability analysis shows high level of similarity between the donors for this data set. Conclusions Histone modifications, rather than DNA methylation, provide the primary epigenetic control of early differentiation of MSCs towards the chondrogenic lineage.
机译：背景技术为了安全地临床应用间充质干细胞（MSC）制造的工程软骨，必须详细了解软骨分化的分子机制。基因表达和细胞外基质合成的变化已被广泛研究，但尚未描述这些变化所基于的表观基因组修饰。为此，我们进行了全基因组染色质免疫沉淀和深度测序，以定量检测六种组蛋白修饰，减少了亚硫酸氢盐的代表性测序，以定量检测DNA在藻酸盐支架中软骨分化7天之前和之后的DNA甲基化和mRNA微阵列，以定量基因表达。为了增加我们观察结果的临床相关性，该研究基于来自四个供体的原代骨髓来源的MSC，从而使我们能够研究个体间的差异。结果我们发现表观遗传标记和基因表达之间存在两个水平的关系。首先，通过转录起始位点附近的H3K4me3和H3K9ac的适度变化，在表观遗传上预先设定了与MSC特性和肌肉骨骼系统遗传相关的大量基因。这些基因大多数保持转录不变。其次，与软骨形成密切相关的转录上调基因在基因体中具有H3K36me3的特征，在启动子和基因的5'端高度增加了H3K4me3和H3K9ac的含量，在每个上调的基因的至少一个增强子区域中标记的H3K27ac和H3K4me1的含量增加。在7天的时间范围内，启动子DNA甲基化的变化与基因表达的变化没有显着相关。捐助者间变异性分析显示，该数据集的捐助者之间具有高度相似性。结论组蛋白修饰而不是DNA甲基化为MSCs向软骨形成谱系的早期分化提供了主要的表观遗传控制。

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