Transcriptional regulation of the human TNFSF11 gene in T cells via a cell type-selective set of distal enhancers.
Transcriptional regulation of the human TNFSF11 gene in T cells via a cell type-selective set of distal enhancers.
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DOI：
10.1002/jcb.24974
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发表时间：
2015-02
影响因子：
4
通讯作者：
Pike, J. Wesley
中科院分区：
文献类型：
--
作者：
Bishop, Kathleen A.;Wang, Xiaohua;Coy, Heidi M.;Meyer, Mark B.;Gumperz, Jenny E.;Pike, J. Wesley
除成骨细胞系细胞外，NF-κB配体的TNF样因子受体激活剂（RANKL）在B和T细胞中表达，可能在骨吸收中发挥作用。小鼠T细胞中的Rankl基因（Tnfsf 11）表达通过多个远端元件介导，所述远端元件通过增加的转录因子占据、组蛋白尾部乙酰化和RNA聚合酶II募集来标记。然而，对T细胞中人TNFSF 11的调节知之甚少。因此，我们研究了T细胞活化对Jurkat细胞和原代人T细胞中该因子表达的影响。然后，我们通过使用ChIP芯片分析扫描TNFSF 11位点周围超过400 kb的DNA以寻找调节增强子来探索这种调节的机制。组蛋白H3/H4乙酰化富集鉴定了位于人类TNFSF 11 TSS上游-170和-220 kb之间的假定调节区，我们将其命名为人类T细胞控制区（hTCCR）。该区域与小鼠TCCR显示出高度的序列保守性。U 0126对MEK 1/2的抑制导致RANKL表达降低，表明通过MEK 1/2的刺激是先决条件。ChIP芯片分析还显示，c-FOS也被招募到hTCCR中。重要的是，人TNFSF 11 D5 a/B（RLD 5 a/B）增强子和hTCCR的区段在TCR活化后介导了稳健的诱导型报道子活性。最后，与以BMD失调为特征的疾病有关的SNP共定位于hTCCR区域。我们得出结论，hTCCR区域包含一组细胞选择性增强子，在人类T细胞中TNFSF 11基因的转录调控中起着不可或缺的作用。
In addition to osteoblast lineage cells, the TNF-like factor receptor activator of NF-κB ligand (RANKL) is expressed in both B and T cells and may play a role in bone resorption. Rankl gene (Tnfsf11) expression in mouse T cells is mediated through multiple distal elements marked by increased transcription factor occupancy, histone tail acetylation, and RNA polymerase II recruitment. Little is known, however, of the regulation of human TNFSF11 in T cells. Accordingly, we examined the consequence of T cell activation on the expression of this factor both in Jurkat cells and in primary human T cells. We then explored the mechanism of this regulation by scanning over 400 kb of DNA surrounding the TNFSF11 locus for regulatory enhancers using ChIP-chip analysis. Histone H3/H4 acetylation enrichment identified putative regulatory regions located between −170 and −220 kb upstream of the human TNFSF11 TSS that we designated the human T cell control region (hTCCR). This region showed high sequence conservation with the mouse TCCR. Inhibition of MEK1/2 by U0126 resulted in decreased RANKL expression suggesting that stimulation through MEK1/2 was a prerequisite. ChIP-chip analysis also revealed that c-FOS was recruited to the hTCCR as well. Importantly, both the human TNFSF11 D5a/b (RLD5a/b) enhancer and segments of the hTCCR mediated robust inducible reporter activity following TCR activation. Finally, SNPs implicated in diseases characterized by dysregulated BMD co-localized to the hTCCR region. We conclude that the hTCCR region contains a cell-selective set of enhancers that plays an integral role in the transcriptional regulation of the TNFSF11 gene in human T cells.
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影响因子：
5.3
作者：
Kim, Sungtae;Yamazaki, Miwa;Pike, J. Wesley
通讯作者：
Pike, J. Wesley
影响因子：
4.4
作者：
Kanamaru, F;Iwai, H;Azuma, M
通讯作者：
Azuma, M
影响因子：
--
作者：
Kim, Sungtae;Yamazaki, Miwa;Pike, J. Wesley
通讯作者：
Pike, J. Wesley
影响因子：
4.8
作者：
Bishop, Kathleen A.;Coy, Heidi M.;Pike, J. Wesley
通讯作者：
Pike, J. Wesley
影响因子：
82.9
作者：
Loser, Karin;Mehling, Annette;Beissert, Stefan
通讯作者：
Beissert, Stefan