Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer
Dissection of transcriptional and cis-regulatory control of differentiation in human pancreatic cancer
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DOI：
10.15252/embj.201592404
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发表时间：
2016-03-15
期刊：
影响因子：
11.4
通讯作者：
Natoli, Gioacchino
中科院分区：
文献类型：
--
作者：
Diaferia, Giuseppe R.;Balestrieri, Chiara;Natoli, Gioacchino
癌的组织学分级描述了肿瘤细胞在分化的上皮结构中组织的能力，并具有预后和治疗影响。在这里，我们表明，差异使用的基因组库的转录增强子，导致在人类胰腺导管腺癌（PDAC）的等级特异性基因表达程序。通过整合不同级别PDAC细胞系中的基因表达谱、表观基因组足迹和功能丧失实验，我们确定了对高级别和低级别PDAC特异性的增强子的库以及用于维持其活性的转录因子的同源集合。在PDAC分化的候选调节因子中，KLF5选择性地在肿瘤前病变和低级别原发性PDAC和细胞系中表达，在那里它维持等级特异性增强子的乙酰化、上皮基因（如角蛋白和粘蛋白）的表达以及在异种移植物中组织腺上皮的能力。PDAC中控制分化的转录因子的鉴定将有助于阐明其异质性和进展的分子基础。
The histological grade of carcinomas describes the ability of tumor cells to organize in differentiated epithelial structures and has prognostic and therapeutic impact. Here, we show that differential usage of the genomic repertoire of transcriptional enhancers leads to grade-specific gene expression programs in human pancreatic ductal adenocarcinoma (PDAC). By integrating gene expression profiling, epigenomic footprinting, and loss-of-function experiments in PDAC cell lines of different grade, we identified the repertoires of enhancers specific to high-and low-grade PDACs and the cognate set of transcription factors acting to maintain their activity. Among the candidate regulators of PDAC differentiation, KLF5 was selectively expressed in pre-neoplastic lesions and low-grade primary PDACs and cell lines, where it maintained the acetylation of grade-specific enhancers, the expression of epithelial genes such as keratins and mucins, and the ability to organize glandular epithelia in xenografts. The identification of the transcription factors controlling differentiation in PDACs will help clarify the molecular bases of its heterogeneity and progression.