Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A
Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation, and Homeostasis by PTF1A
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DOI：
10.1128/mcb.00358-16
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发表时间：
2016-12-01
影响因子：
5.3
通讯作者：
MacDonald, Raymond J.
中科院分区：
文献类型：
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作者：
Hoang, Chinh Q.;Hale, Michael A.;MacDonald, Raymond J.
维持细胞类型的身份对健康至关重要，但对维持分化表型长期稳定的调节知之甚少。为了研究关键转录调节因子在成人分化细胞中的作用，我们在体内研究了发育主调节因子PTF1A的缺失对成年胰腺腺泡细胞特化表型的影响。转录组测序和染色质免疫沉淀测序结果显示，PTF1A维持了所有细胞过程中专门用于分泌消化酶的基因表达，高度调节了对未折叠蛋白的监视，并提高了未折叠蛋白反应（UPR）。PTF1A的控制直接作用于靶基因，并通过一个由10个成员组成的转录因子网络间接进行。PTF1A的缺失导致失衡，从而压倒UPR，诱导细胞损伤，并引发腺泡化生。细胞身份受损发生在特异性胃基因的抑制，其中一些也与胰腺导管细胞有关。腺泡细胞稳态、分化和身份的丧失与胰腺炎和胰腺腺癌的病理直接相关。
Maintenance of cell type identity is crucial for health, yet little is known of the regulation that sustains the long-term stability of differentiated phenotypes. To investigate the roles that key transcriptional regulators play in adult differentiated cells, we examined the effects of depletion of the developmental master regulator PTF1A on the specialized phenotype of the adult pancreatic acinar cell in vivo. Transcriptome sequencing and chromatin immunoprecipitation sequencing results showed that PTF1A maintains the expression of genes for all cellular processes dedicated to the production of the secretory digestive enzymes, a highly attuned surveillance of unfolded proteins, and a heightened unfolded protein response (UPR). Control by PTF1A is direct on target genes and indirect through a ten-member transcription factor network. Depletion of PTF1A causes an imbalance that overwhelms the UPR, induces cellular injury, and provokes acinar metaplasia. Compromised cellular identity occurs by derepression of characteristic stomach genes, some of which are also associated with pancreatic ductal cells. The loss of acinar cell homeostasis, differentiation, and identity is directly relevant to the pathologies of pancreatitis and pancreatic adenocarcinoma.