Background and aims c-Myc is highly expressed in pancreatic multipotent progenitor cells (MPC) and in pancreatic cancer. The transition from MPC to unipotent acinar progenitors is associated with c-Myc downregulation; a role for c-Myc in this process, and its possible relationship to a role in cancer, has not been established. Design Using coimmunoprecipitation assays, we demonstrate that c-Myc and Ptf1a interact. Using reverse transcriptase qPCR, western blot and immunofluorescence, we show the erosion of the acinar programme. To analyse the genomic distribution of c-Myc and Ptf1a and the global transcriptomic profile, we used ChIP-seq and RNA-seq, respectively; validation was performed with ChIP-qPCR and RT-qPCR. Lineage-tracing experiments were used to follow the effect of c-Myc overexpression in preacinar cells on acinar differentiation. Results c-Myc binds and represses the transcriptional activity of Ptf1a. c-Myc overexpression in preacinar cells leads to a massive erosion of differentiation. In adult Ela1-Myc mice: (1) c-Myc binds to Ptf1a, and Tcf3 is downregulated; (2) Ptf1a and c-Myc display partially overlapping chromatin occupancy but do not bind the same E-boxes; (3) at the proximal promoter of genes coding for digestive enzymes, we find reduced PTF1 binding and increased levels of repressive chromatin marks and PRC2 complex components. Lineage tracing of committed acinar precursors reveals that c-Myc overexpression does not restore multipotency but allows the persistence of a preacinar-like cell population. In addition, mutant KRas can lead to c-Myc overexpression and acinar dysregulation. Conclusions c-Myc repression during development is crucial for the maturation of preacinar cells, and c-Myc overexpression can contribute to pancreatic carcinogenesis through the induction of a dedifferentiated state.

中文翻译：

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c-Myc 下调是腺泡前到腺泡成熟和胰腺稳态所必需的

背景和目的 c-Myc 在胰腺多能祖细胞 (MPC) 和胰腺癌中高度表达。从 MPC 到单能腺泡祖细胞的转变与 c-Myc 下调有关；尚未确定 c-Myc 在此过程中的作用及其与癌症作用的可能关系。设计 使用共免疫沉淀分析，我们证明了 c-Myc 和 Ptf1a 相互作用。使用逆转录酶 qPCR、蛋白质印迹和免疫荧光，我们显示了腺泡程序的侵蚀。为了分析 c-Myc 和 Ptf1a 的基因组分布以及全局转录组谱，我们分别使用了 ChIP-seq 和 RNA-seq；使用 ChIP-qPCR 和 RT-qPCR 进行验证。谱系追踪实验用于跟踪前腺泡细胞中 c-Myc 过表达对腺泡分化的影响。结果 c-Myc 结合并抑制 Ptf1a 的转录活性。c-Myc 在前腺细胞中的过度表达导致分化的大量侵蚀。在成年 Ela1-Myc 小鼠中：（1）c-Myc 与 Ptf1a 结合，Tcf3 下调；(2) Ptf1a 和 c-Myc 显示部分重叠的染色质占用，但不结合相同的 E-box；(3) 在编码消化酶的基因的近端启动子处，我们发现 PTF1 结合减少，抑制性染色质标记和 PRC2 复合成分的水平增加。定型腺泡前体的谱系追踪表明 c-Myc 过表达不会恢复多能性，但允许前腺泡样细胞群持续存在。此外，突变的 KRas 可导致 c-Myc 过度表达和腺泡失调。