A single transcription factor is sufficient to induce and maintain secretory cell architecture.
A single transcription factor is sufficient to induce and maintain secretory cell architecture.
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DOI：
10.1101/gad.285684.116
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发表时间：
2017-01-15
影响因子：
10.5
通讯作者：
Mills JC
中科院分区：
文献类型：
--
作者：
Lo HG;Jin RU;Sibbel G;Liu D;Karki A;Joens MS;Madison BB;Zhang B;Blanc V;Fitzpatrick JA;Davidson NO;Konieczny SF;Mills JC
在这里，Lo等人证明细胞结构可以由一个独立于指定细胞身份的程序的发育调节转录程序控制。他们发现MIST1 （BHLHA15）是一个“比例因子”，在执行调节分泌的细胞中普遍建立分泌形态，并且靶向删除MIST1会导致多种外分泌细胞的分泌装置拆除。我们假设基本螺旋-环-螺旋（bHLH） MIST1 （BHLHA15）是一个“比例因子”，在执行调节分泌的细胞中普遍建立分泌形态。在这里，我们发现MIST1的靶向删除导致多种外分泌细胞的分泌装置的拆除。壁细胞（PCs）的功能是将酸泵入胃中，通常缺乏MIST1，不进行调节分泌。在PCs中强行表达MIST1导致它们的顶端细胞质扩大，线粒体/溶酶体运输重排，并产生大的分泌颗粒。Mist1在多个器官中诱导了一系列由Mist1调控的基因，但不影响PC功能。MIST1在调节自噬体/溶酶体降解、线粒体运输和氨基酸代谢的基因的第一个内含子中结合CATATG/CAGCTG E盒子。在肝细胞中，异位诱导MIST1也会引起细胞结构和基因表达的类似改变。因此，MIST1本身是诱导和维持分泌细胞结构所必需和充分的比例因子。我们的研究结果表明，尽管每个器官中的成熟细胞类型可能具有独特的发育起源，但在整个身体中执行相似生理功能的细胞共享相似的转录因子介导的结构“蓝图”。
Here, Lo et al. demonstrate that cell architecture can be controlled by a developmentally regulated transcriptional program independent of the program that specifies cell identity. They show that MIST1 (BHLHA15) is a “scaling factor” that universally establishes secretory morphology in cells that perform regulated secretion, and targeted deletion of MIST1 causes dismantling of the secretory apparatus of diverse exocrine cells. We hypothesized that basic helix–loop–helix (bHLH) MIST1 (BHLHA15) is a “scaling factor” that universally establishes secretory morphology in cells that perform regulated secretion. Here, we show that targeted deletion of MIST1 caused dismantling of the secretory apparatus of diverse exocrine cells. Parietal cells (PCs), whose function is to pump acid into the stomach, normally lack MIST1 and do not perform regulated secretion. Forced expression of MIST1 in PCs caused them to expand their apical cytoplasm, rearrange mitochondrial/lysosome trafficking, and generate large secretory granules. Mist1 induced a cohort of genes regulated by MIST1 in multiple organs but did not affect PC function. MIST1 bound CATATG/CAGCTG E boxes in the first intron of genes that regulate autophagosome/lysosomal degradation, mitochondrial trafficking, and amino acid metabolism. Similar alterations in cell architecture and gene expression were also caused by ectopically inducing MIST1 in vivo in hepatocytes. Thus, MIST1 is a scaling factor necessary and sufficient by itself to induce and maintain secretory cell architecture. Our results indicate that, whereas mature cell types in each organ may have unique developmental origins, cells performing similar physiological functions throughout the body share similar transcription factor-mediated architectural “blueprints.”