A systems biology approach identifies a regulatory network in parotid acinar cell terminal differentiation.
A systems biology approach identifies a regulatory network in parotid acinar cell terminal differentiation.
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DOI：
10.1371/journal.pone.0125153
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Darling DS
中科院分区：
文献类型：
--
作者：
Metzler MA;Venkatesh SG;Lakshmanan J;Carenbauer AL;Perez SM;Andres SA;Appana S;Brock GN;Wittliff JL;Darling DS
驱动腮腺祖细胞终末分化的转录因子网络在很大程度上仍然未知，并且对于理解再生过程至关重要。采用系统生物学方法测量大鼠腮腺腺泡细胞终末分化过程中体内mRNA和microRNA的表达。激光捕获显微切割（LCM）被用来专门分离腺泡细胞RNA的时间跨越一个月的腮腺分化期。微阵列测量的聚类表明表达发生在四个阶段。mRNA表达模式表明Pparg的一种新作用，它在出生后中期分化过程中与几种靶基因mRNA一起短暂增加。79种microRNA随时间显著差异表达。mRNA表达的统计学显著变化的概况，结合microRNA及其靶mRNA的相互关系，表明涉及Klf 4的假定网络，Klf 4是一种分化抑制转录因子，其随着几种靶向microRNA在分化后期的增加而减少。该网络表明，分子开关（涉及Prdm 1，Sox 11，Pax 5，miR-200 a和miR-30 a）逐渐减少Xbp 1基因转录的抑制，与miR-214的翻译抑制减少一致。转录因子Xbp 1 mRNA最初较低，逐渐增加，并可通过与Atf 6的正反馈回路维持。转染研究表明，Xbp 1 Mist 1启动子。此外，Xbp 1和Mist 1各自激活腮腺分泌蛋白（Psp）基因，该基因编码丰富的唾液蛋白，并且是终末分化的标志物。本研究鉴定了腮腺腺泡细胞分化过程中Pparg、Klf 4和Sox 11的新表达模式，以及许多差异表达的microRNA。网络分析确定了一个新的干性臂，一个涉及转录因子和microRNA的遗传开关，并过渡到Xbp 1驱动的分化网络。该网络提示腮腺终末分化中的关键调控相互作用。
The transcription factor networks that drive parotid salivary gland progenitor cells to terminally differentiate, remain largely unknown and are vital to understanding the regeneration process. A systems biology approach was taken to measure mRNA and microRNA expression in vivo across acinar cell terminal differentiation in the rat parotid salivary gland. Laser capture microdissection (LCM) was used to specifically isolate acinar cell RNA at times spanning the month-long period of parotid differentiation. Clustering of microarray measurements suggests that expression occurs in four stages. mRNA expression patterns suggest a novel role for Pparg which is transiently increased during mid postnatal differentiation in concert with several target gene mRNAs. 79 microRNAs are significantly differentially expressed across time. Profiles of statistically significant changes of mRNA expression, combined with reciprocal correlations of microRNAs and their target mRNAs, suggest a putative network involving Klf4, a differentiation inhibiting transcription factor, which decreases as several targeting microRNAs increase late in differentiation. The network suggests a molecular switch (involving Prdm1, Sox11, Pax5, miR-200a, and miR-30a) progressively decreases repression of Xbp1 gene transcription, in concert with decreased translational repression by miR-214. The transcription factor Xbp1 mRNA is initially low, increases progressively, and may be maintained by a positive feedback loop with Atf6. Transfection studies show that Xbp1Mist1 promoter. In addition, Xbp1 and Mist1 each activate the parotid secretory protein (Psp) gene, which encodes an abundant salivary protein, and is a marker of terminal differentiation. This study identifies novel expression patterns of Pparg, Klf4, and Sox11 during parotid acinar cell differentiation, as well as numerous differentially expressed microRNAs. Network analysis identifies a novel stemness arm, a genetic switch involving transcription factors and microRNAs, and transition to an Xbp1 driven differentiation network. This proposed network suggests key regulatory interactions in parotid gland terminal differentiation.
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影响因子：
4.3
作者：
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