TENET 2.0: Identification of key transcriptional regulators and enhancers in lung adenocarcinoma.
TENET 2.0: Identification of key transcriptional regulators and enhancers in lung adenocarcinoma.
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DOI：
10.1371/journal.pgen.1009023
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发表时间：
2020-09
期刊：
影响因子：
4.5
通讯作者：
Rhie SK
中科院分区：
文献类型：
--
作者：
Mullen DJ;Yan C;Kang DS;Zhou B;Borok Z;Marconett CN;Farnham PJ;Offringa IA;Rhie SK
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。虽然基因改变已被确定为肺腺癌亚群的驱动因素，但它们不能完全解释肿瘤的发展。表观遗传学改变与肿瘤的发病机制有关。为了鉴定驱动肺腺癌的表观遗传改变，我们在原代正常肺和肺腺癌细胞中使用了使用表观遗传性状方法（TENET 2.0）的追踪增强子网络的改进版本。我们发现超过32，000个增强子在正常肺和肺腺癌之间表现出差异激活。在肺腺癌与正常肺中失活的已鉴定转录调节因子中，NKX 2 -1与大量沉默的增强子相关。在所鉴定的激活的转录调节因子中，CENPA、FOXM 1和MYBL 2与许多癌症特异性增强子相关联。CENPA、FOXM 1和MYBL 2的高表达尤其在肺腺癌亚组中观察到，并且与患者存活率差相关。值得注意的是，CENPA、FOXM 1和MYBL 2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、FOXM 1或MYBL 2相关的与患者生存率低相关的单个肺腺癌增强子。FOXM 1和MYBL 2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TK 1（MYBL 2连接增强子的潜在靶基因）的表达与患者生存率低相关。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的见解，突出了临床干预的新的潜在靶点。虽然基因改变已被确定为肺腺癌亚群的驱动因素，但它们不能完全解释肿瘤的发展。在这里，我们研究了可能导致肺腺癌进展的表观遗传学改变。我们使用了一种称为TENET 2.0的生物信息学方法，以确定与正常肺相比，肺腺癌中改变的关键调节子和增强子。我们确定NKX 2 -1是肺腺癌中失活的转录调节因子，与癌症中大量沉默的增强子相关。在激活的转录调节因子中，CENPA、MYBL 2和FOXM 1与许多癌症特异性增强子相关，并且在显示患者存活率差的肺腺癌亚组中观察到这些调节因子的高表达。通过研究这些关键调控因子的下游效应，我们还确定了与生存相关的单个增强子及其潜在的靶基因，包括TK 1。我们的研究结果表明，关键调控因子的异常表达驱动了肺腺癌的表观遗传失调，促进了新的生物标志物和治疗靶点的未来发展。
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. Although genetic alterations have been identified as drivers in subsets of lung adenocarcinoma, they do not fully explain tumor development. Here we investigated epigenetic alterations that might contribute to lung adenocarcinoma progression. We used a bioinformatics approach called TENET 2.0 to identify key regulators and enhancers altered in lung adenocarcinoma compared to normal lung. We identified NKX2-1 as a transcriptional regulator inactivated in lung adenocarcinoma, linked to a large number of enhancers silenced in cancer. Among the activated transcriptional regulators, CENPA, MYBL2, and FOXM1 were linked to numerous cancer-specific enhancers and high expression of these regulators was observed in a subgroup of lung adenocarcinomas showing poor patient survival. Investigating downstream effects of these key regulators, we also determined individual enhancers associated with survival and their potential target genes, including TK1. Our findings suggest that abnormal expression of key regulators drives epigenetic deregulation in lung adenocarcinoma, promoting future development of novel biomarkers and therapeutic targets.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
50.3
作者：
Guler, Gulfem Dilek;Tindell, Charles Albert;Classon, Marie
通讯作者：
Classon, Marie
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H