FOXA2 controls the cis-regulatory networks of pancreatic cancer cells in a differentiation grade-specific manner.,The EMBO Journal

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FOXA2 controls the cis-regulatory networks of pancreatic cancer cells in a differentiation grade-specific manner.
The EMBO Journal ( IF 9.4 ) Pub Date : 2019-09-17 , DOI: 10.15252/embj.2019102161
Marta Milan _{1,

2,

3} , Chiara Balestrieri _{1,

2} , Gabriele Alfarano _{1,

2} , Sara Polletti _{1,

2} , Elena Prosperini _{1,

2} , Paola Spaggiari ₂ , Alessandro Zerbi _{1,

2} , Giuseppe R Diaferia ₃ , Gioacchino Natoli _{1,

2}

Affiliation

Differentiation of normal and tumor cells is controlled by regulatory networks enforced by lineage-determining transcription factors (TFs). Among them, TFs such as FOXA1/2 bind naïve chromatin and induce its accessibility, thus establishing new gene regulatory networks. Pancreatic ductal adenocarcinoma (PDAC) is characterized by the coexistence of well- and poorly differentiated cells at all stages of disease. How the transcriptional networks determining such massive cellular heterogeneity are established remains to be determined. We found that FOXA2, a TF controlling pancreas specification, broadly contributed to the cis-regulatory networks of PDACs. Despite being expressed in both well- and poorly differentiated PDAC cells, FOXA2 displayed extensively different genomic distributions and controlled distinct gene expression programs. Grade-specific functions of FOXA2 depended on its partnership with TFs whose expression varied depending on the differentiation grade. These data suggest that FOXA2 contributes to the regulatory networks of heterogeneous PDAC cells via interactions with alternative partner TFs.

中文翻译：

FOXA2以分化等级特异性方式控制胰腺癌细胞的顺式调控网络。

正常细胞和肿瘤细胞的分化受谱系确定转录因子（TFs）强制的调节网络控制。其中，诸如FOXA1 / 2的TF结合幼稚的染色质并诱导其可及性，从而建立了新的基因调控网络。胰腺导管腺癌（PDAC）的特征是，在疾病的所有阶段，分化良好的细胞和分化较弱的细胞并存。如何建立确定这种大量细胞异质性的转录网络还有待确定。我们发现FOXA2，TF控制胰腺规范，广泛地促进了PDAC的顺式调节网络。尽管FOXA2在高分化和低分化的PDAC细胞中均表达，但它们显示出广泛不同的基因组分布并控制着不同的基因表达程序。FOXA2的特定于等级的功能取决于其与TF的伙伴关系，TF的表达根据分化等级而变化。这些数据表明FOXA2通过与替代伴侣TF的相互作用，促进了异质PDAC细胞的调控网络。

更新日期：2019-10-16

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