Integrative multi-omics analysis of intestinal organoid differentiation
Integrative multi-omics analysis of intestinal organoid differentiation
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DOI：
10.15252/msb.20188227
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发表时间：
2018-06-01
影响因子：
9.9
通讯作者：
Vermeulen, Michiel
中科院分区：
文献类型：
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作者：
Lindeboom, Rik G. H.;van Voorthuijsen, Lisa;Vermeulen, Michiel
肠类器官准确地再现了体内上皮稳态，从而代表了研究谱系规范和细胞分化的强大体外系统。在这里，我们在干细胞富集和干细胞耗尽的小鼠肠道类器官上应用了多组学框架，以获得成人肠道干细胞分化过程中驱动差异基因表达的分子机制的整体视图。我们的数据揭示了肠干细胞和肠上皮细胞之间转录组和蛋白质组的整体重新布线，大多数动态蛋白质表达是转录驱动的。整合绝对 mRNA 和蛋白质拷贝数揭示了基因表达的转录后调控。通过探索表观遗传景观，发现了大量细胞类型特异性的调控元件，这表明 Hnf4g 是肠上皮细胞分化的主要驱动因素。总之，通过应用综合系统生物学方法，我们发现了多层基因表达调控，这有助于小鼠小肠上皮的谱系规范和可塑性。
Intestinal organoids accurately recapitulate epithelial homeostasis invivo, thereby representing a powerful invitro system to investigate lineage specification and cellular differentiation. Here, we applied a multi-omics framework on stem cell-enriched and stem cell-depleted mouse intestinal organoids to obtain a holistic view of the molecular mechanisms that drive differential gene expression during adult intestinal stem cell differentiation. Our data revealed a global rewiring of the transcriptome and proteome between intestinal stem cells and enterocytes, with the majority of dynamic protein expression being transcription-driven. Integrating absolute mRNA and protein copy numbers revealed post-transcriptional regulation of gene expression. Probing the epigenetic landscape identified a large number of cell-type-specific regulatory elements, which revealed Hnf4g as a major driver of enterocyte differentiation. In summary, by applying an integrative systems biology approach, we uncovered multiple layers of gene expression regulation, which contribute to lineage specification and plasticity of the mouse small intestinal epithelium.