Chromatin remodeling: recruitment of histone demethylase RBP2 by Mad1 for transcriptional repression of a Myc target gene, telomerase reverse transcriptase
Chromatin remodeling: recruitment of histone demethylase RBP2 by Mad1 for transcriptional repression of a Myc target gene, telomerase reverse transcriptase
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DOI：
10.1096/fj.09-140087
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发表时间：
2010-02-01
期刊：
影响因子：
4.8
通讯作者：
Xu, Dawei
中科院分区：
文献类型：
--
作者：
Ge, Zheng;Li, Wenjuan;Xu, Dawei
已知Myc/Max/Mad网络转录因子通过募集组蛋白乙酰转移酶或脱乙酰酶来调控靶基因的表达。在本研究中，我们发现Mad1将组蛋白去甲基酶RBP2招募到Myc靶向端粒酶逆转录酶(HTERT)基因启动子来抑制转录。随着白血病HL60细胞的分化，MAD1和RBP2均上调表达，相互作用，共同占据hTERT启动子，伴随组蛋白H3-K4去甲基化。在永生化p493-6 B细胞中，关闭c-Myc导致hTERT启动子Mad1和RBP2积聚，hTERT mRNA表达减弱。当RBP2缺失时，p493-6细胞中hTERT的表达显著增强，并伴随着RBP2与hTERT启动子H3-K4甲基化的解离和增加。此外，在hTERT基因沉默的人成纤维细胞中，hTERT启动子上存在RBP2和Mad1，而RBP2缺失会导致基因去抑制。综上所述，Mad1将RBP2招募到hTERT启动子，进而使H3-K4去甲基化，从而有助于在正常或分化的恶性肿瘤细胞中稳定抑制hTERT基因。我们的发现揭示了Myc/Max/Mad网络蛋白控制其目标基因转录的新机制，并为端粒酶沉默和激活的潜在机制提供了洞察力。-GE，Z.，Li，W.，Wang，N.，Liu，C.，朱，Q，Bjorkholm，M.，Gruber，A.，Xu，D.染色质重塑：Mad1招募组蛋白去甲基酶RBP2，以转录抑制Myc目标基因，端粒酶逆转录酶。FASE B J.24,579-586(2010)。Www.fasebj.org
The Myc/Max/Mad network transcription factors are known to govern target gene expression through recruiting histone acetyltransferases or deacetylases. In the present study, we show that Mad1 recruits the histone demethylase RBP2 to the Myc target telomerase reverse transcriptase (hTERT) gene promoter to repress transcription. With differentiation of leukemic HL60 cells, Mad1 and RBP2 were both up-regulated, interacted, and cooccupied the hTERT promoter accompanied by histone H3-K4 demethylation. In immortalized p493-6 B cells, shutting down c-Myc led to the accumulation of Mad1 and RBP2 at hTERT promoter and diminished hTERT mRNA expression. When RBP2 was depleted, hTERT expression was significantly enhanced, coupled with dissociation of RBP2 with and increased H3-K4 methylation at the hTERT promoter in p493-6 cells. Moreover, RBP2 and Mad1 were present on the hTERT promoter in human fibroblasts having a silent hTERT gene, and RBP2 depletion resulted in gene derepression. Taken together, Mad1 recruits RBP2 to the hTERT promoter that, in turn, demethylates H3-K4, thereby contributing to a stable repression of the hTERT gene in normal or differentiated malignant cells. Our findings reveal a novel mechanism through which the Myc/Max/Mad network proteins control their target gene transcription and provide insights into mechanisms underlying telomerase silencing and activation.-Ge, Z., Li, W., Wang, N., Liu, C., Zhu, Q., Bjorkholm, M., Gruber, A., Xu, D. Chromatin remodeling: recruitment of histone demethylase RBP2 by Mad1 for transcriptional repression of a Myc target gene, telomerase reverse transcriptase. FASEB J. 24, 579-586 (2010). www.fasebj.org