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TENET 2.0: Identification of key transcriptional regulators and enhancers in lung adenocarcinoma.
PLOS Genetics ( IF 4.0 ) Pub Date : 2020-09-14 , DOI: 10.1371/journal.pgen.1009023
Daniel J Mullen 1, 2 , Chunli Yan 1, 2 , Diane S Kang 1, 2 , Beiyun Zhou 3 , Zea Borok 1, 3 , Crystal N Marconett 1, 2 , Peggy J Farnham 1 , Ite A Offringa 1, 2 , Suhn Kyong Rhie 1
Affiliation  

Lung cancer is the leading cause of cancer-related death and lung adenocarcinoma is its most common subtype. Although genetic alterations have been identified as drivers in subsets of lung adenocarcinoma, they do not fully explain tumor development. Epigenetic alterations have been implicated in the pathogenesis of tumors. To identify epigenetic alterations driving lung adenocarcinoma, we used an improved version of the Tracing Enhancer Networks using Epigenetic Traits method (TENET 2.0) in primary normal lung and lung adenocarcinoma cells. We found over 32,000 enhancers that appear differentially activated between normal lung and lung adenocarcinoma. Among the identified transcriptional regulators inactivated in lung adenocarcinoma vs. normal lung, NKX2-1 was linked to a large number of silenced enhancers. Among the activated transcriptional regulators identified, CENPA, FOXM1, and MYBL2 were linked to numerous cancer-specific enhancers. High expression of CENPA, FOXM1, and MYBL2 is particularly observed in a subgroup of lung adenocarcinomas and is associated with poor patient survival. Notably, CENPA, FOXM1, and MYBL2 are also key regulators of cancer-specific enhancers in breast adenocarcinoma of the basal subtype, but they are associated with distinct sets of activated enhancers. We identified individual lung adenocarcinoma enhancers linked to CENPA, FOXM1, or MYBL2 that were associated with poor patient survival. Knockdown experiments of FOXM1 and MYBL2 suggest that these factors regulate genes involved in controlling cell cycle progression and cell division. For example, we found that expression of TK1, a potential target gene of a MYBL2-linked enhancer, is associated with poor patient survival. Identification and characterization of key transcriptional regulators and associated enhancers in lung adenocarcinoma provides important insights into the deregulation of lung adenocarcinoma epigenomes, highlighting novel potential targets for clinical intervention.



中文翻译:


TENET 2.0:肺腺癌中关键转录调节子和增强子的鉴定。



肺癌是癌症相关死亡的主要原因,肺腺癌是其最常见的亚型。尽管基因改变已被确定为肺腺癌亚型的驱动因素,但它们并不能完全解释肿瘤的发展。表观遗传改变与肿瘤的发病机制有关。为了识别导致肺腺癌的表观遗传改变,我们在原发性正常肺和肺腺癌细胞中使用了改进版的追踪增强网络,采用表观遗传特征方法 (TENET 2.0)。我们发现超过 32,000 个增强子在正常肺和肺腺癌中表现出不同程度的激活。在已确定的转录调节因子中,肺腺癌肺腺癌中失活。在正常肺中,NKX2-1与大量沉默的增强子相关。在已识别的激活转录调节因子中,CENPA、FOXM1 和 MYBL2 与许多癌症特异性增强子相关。 CENPA、FOXM1 和 MYBL2 的高表达在肺腺癌亚组中尤其明显,并且与患者生存率较差相关。值得注意的是,CENPA、FOXM1 和 MYBL2 也是基底亚型乳腺癌中癌症特异性增强子的关键调节因子,但它们与不同的激活增强子组相关。我们确定了与 CENPA、FOXM1 或 MYBL2 相关的个体肺腺癌增强子,这些增强子与患者生存率较差相关。 FOXM1 和 MYBL2 的敲低实验表明,这些因子调节参与控制细胞周期进程和细胞分裂的基因。例如,我们发现TK1 (MYBL2 相关增强子的潜在靶基因)的表达与患者生存率较差相关。 肺腺癌中关键转录调节因子和相关增强子的鉴定和表征为肺腺癌表观基因组的失调提供了重要见解,突出了临床干预的新潜在靶标。

更新日期:2020-09-15
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