PU.1 and C/EBPα synergistically program distinct response to NF-κB activation through establishing monocyte specific enhancers
PU.1 and C/EBPα synergistically program distinct response to NF-κB activation through establishing monocyte specific enhancers
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DOI：
10.1073/pnas.1017214108
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发表时间：
2011-03-29
影响因子：
11.1
通讯作者：
Natarajan, Rama
中科院分区：
文献类型：
--
作者：
Jin, Fulai;Li, Yan;Natarajan, Rama
解开由不同细胞类型编码的转录程序的复杂性一直是细胞生物学的中心目标之一。通过全基因组定位分析，我们研究了两种不同的细胞类型如何对NF-κ B信号通路产生不同的反应。我们发现，TNF-α治疗后，NF-κ B p65亚基结合到不同的基因组位置，随后诱导不同的基因亚群在人单核细胞THP-1细胞与HeLa细胞。有趣的是，两种细胞类型中的差异p65结合与TNF-α刺激前预先存在的细胞类型特异性增强子相关，以组蛋白修饰为标志。我们还发现两种转录因子PU.1和C/EBP α似乎协同介导增强子的产生并影响THP-1细胞中NF-κ B靶向选择。在HeLa细胞中，PU.1和C/EBP α的共表达赋予TNF-α对THP-1特异性NF-κ B靶基因亚组的反应性。这些结果表明，哺乳动物细胞中的转录程序的多样性，至少部分地，从预先存在的增强子，建立细胞特异性转录因子。
Unraveling the complexity of transcriptional programs coded by different cell types has been one of the central goals of cell biology. By using genome-wide location analysis, we examined how two different cell types generate different responses to the NF-kappa B signaling pathway. We showed that, after TNF-alpha treatment, the NF-kappa B p65 subunit binds to distinct genome locations and subsequently induces different subsets of genes in human monocytic THP-1 cells versus HeLa cells. Interestingly, the differential p65 binding in two cell types correlates with preexisting cell type-specific enhancers before TNF-alpha stimulation, marked by histone modifications. We also found that two transcription factors, PU.1 and C/EBP alpha, appear to synergistically mediate enhancer creation and affect NF-kappa B target selection in THP-1 cells. In HeLa cells, coexpression of PU.1 and C/EBP alpha conferred TNF-alpha responsiveness to a subset of THP-1-specific NF-kappa B target genes. These results suggest that the diversity of transcriptional programs in mammalian cells arises, at least in part, from preexisting enhancers that are established by cell-specific transcription factors.