PDF(Pubmed)
Abstract：
Human tissue surfaces are coated with mucins, a family of macromolecular sugar-laden proteins serving diverse functions from lubrication to the formation of selective biochemical barriers against harmful microorganisms and molecules. Membrane mucins are a distinct group of mucins that are attached to epithelial cell surfaces where they create a dense glycocalyx facing the extracellular environment. All mucin proteins carry long stretches of tandemly repeated sequences that undergo extensive O-linked glycosylation to form linear mucin domains. However, the repetitive nature of mucin domains makes them prone to recombination and renders their genetic sequences particularly difficult to read with standard sequencing technologies. As a result, human mucin genes suffer from significant sequence gaps that have hampered the investigation of gene function in health and disease. Here we leveraged a recent human genome assembly to characterize a previously unmapped MUC3B gene located at the q22 locus on chromosome 7, within a cluster of four structurally related membrane mucin genes that we name the MUC3 cluster. We found that MUC3B shares high sequence identity with the known MUC3A gene and that the two genes are governed by evolutionarily conserved regulatory elements. Furthermore, we show that MUC3A, MUC3B, MUC12, and MUC17 in the human MUC3 cluster are expressed in intestinal epithelial cells (IECs). Our results complete existing genetic gaps in the MUC3 cluster which is a conserved genetic unit in vertebrates. We anticipate our results to be the starting point for the detection of disease-associated polymorphisms in the human MUC3 cluster. Moreover, our study provides the basis for the exploration of intestinal mucin gene function in widely used experimental models such as human intestinal organoids and genetic mouse models.
摘要：
人体组织表面涂有粘液，一类高分子含糖蛋白质，具有多种功能，从润滑到形成针对有害微生物和分子的选择性生化屏障。膜粘蛋白是一组不同的粘蛋白，它们附着在上皮细胞表面，在那里它们产生面向细胞外环境的致密糖萼。所有粘蛋白蛋白都携带长的串联重复序列，这些序列经历广泛的O-连接糖基化以形成线性粘蛋白结构域。然而,粘蛋白结构域的重复性质使它们易于重组，并使它们的遗传序列特别难以用标准测序技术读取。因此,人类粘蛋白基因存在明显的序列缺口，这阻碍了对健康和疾病中基因功能的研究。在这里，我们利用最近的人类基因组组装来表征位于7号染色体q22基因座的先前未映射的MUC3B基因，在四个结构相关的膜粘蛋白基因簇中，我们将其命名为MUC3簇。我们发现MUC3B与已知的MUC3A基因具有很高的序列同一性，并且这两个基因由进化上保守的调节元件控制。此外，我们显示MUC3A，MUC3B,人MUC3簇中的MUC12和MUC17在肠上皮细胞(IECs)中表达。我们的结果完成了MUC3簇中现有的遗传缺口，MUC3簇是脊椎动物中的保守遗传单元。我们预计我们的结果将成为检测人类MUC3簇中疾病相关多态性的起点。此外，本研究为人类肠道类器官和遗传小鼠模型等广泛使用的实验模型探索肠道粘蛋白基因功能提供了依据。
