Fli1 represses transcription of the human α2(I) collagen gene by recruitment of the HDAC1/p300 complex.
Fli1 represses transcription of the human α2(I) collagen gene by recruitment of the HDAC1/p300 complex.
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DOI：
10.1371/journal.pone.0074930
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Trojanowska M
中科院分区：
文献类型：
--
作者：
Asano Y;Trojanowska M
Fli 1是Ets转录因子家族的成员，是人α2（I）胶原（COL 1A 2）基因的关键阻遏物。虽然我们以前的研究已经描述了TGF-β通过连续的翻译后修饰诱导Fli 1从COL 1A 2启动子的置换，但Fli 1作为COL 1A 2基因的有效转录抑制因子的详细机制尚未得到充分研究。为了解决这个问题，我们进行了一系列的实验，特别是集中在蛋白质-蛋白质相互作用和表观遗传转录调控。串联亲和纯化和质谱的组合鉴定HDAC 1为Fli 1相互作用蛋白。在静止条件下，HDAC 1诱导Fli 1的脱乙酰化，导致Fli 1 DNA结合能力的增加，而p300通过促进Fli 1-HDAC 1-p300复合物的形成来增强这一过程。TGF-β诱导的Fli 1在苏氨酸312处的磷酸化导致该蛋白复合物的分解。在静止的真皮成纤维细胞中，Fli 1、HDAC 1和p300占据了COL 1A 2启动子的−404至−237区域，包括Fli 1结合位点。TGF-β诱导Fli 1和HDAC 1从COL 1A 2启动子解离，同时促进Ets 1和p300募集。此外，在COL 1A 2启动子中Fli 1结合位点周围的组蛋白H3的乙酰化水平与Fli 1和HDAC 1的DNA占有率呈负相关，而与Ets 1和p300呈正相关。在功能研究中，HDAC 1过表达放大了Fli 1对COL 1A 2启动子的抑制作用。此外，恩替司他对HDAC 1的药理学阻断增强了真皮成纤维细胞中的胶原蛋白产生。总的来说，这些结果表明，在静止条件下，Fli 1将HDAC 1/p300募集到COL 1A 2启动子，并通过组蛋白脱乙酰化进行染色质重塑来抑制COL 1A 2基因的表达。Fli 1在苏氨酸312处的TGF-β依赖性磷酸化是调节Fli 1转录阻遏物复合物重塑的关键步骤，导致COL 1A 2基因的转录激活。
Fli1, a member of the Ets transcription factor family, is a key repressor of the human α2(I) collagen (COL1A2) gene. Although our previous studies have delineated that TGF-β induces displacement of Fli1 from the COL1A2 promoter through sequential post-translational modifications, the detailed mechanism by which Fli1 functions as a potent transcriptional repressor of the COL1A2 gene has not been fully investigated. To address this issue, we carried out a series of experiments especially focusing on protein-protein interaction and epigenetic transcriptional regulation. The combination of tandem affinity purification and mass spectrometry identified HDAC1 as a Fli1 interacting protein. Under quiescent conditions, HDAC1 induced deacetylation of Fli1 resulting in an increase of Fli1 DNA binding ability and p300 enhanced this process by promoting the formation of a Fli1-HDAC1-p300 complex. TGF-β-induced phosphorylation of Fli1 at threonine 312 led to disassembly of this protein complex. In quiescent dermal fibroblasts Fli1, HDAC1, and p300 occupied the −404 to −237 region, including the Fli1 binding site, of the COL1A2 promoter. TGF-β induced Fli1 and HDAC1 dissociation from the COL1A2 promoter, while promoting Ets1 and p300 recruitment. Furthermore, acetylation levels of histone H3 around the Fli1 binding site in the COL1A2 promoter inversely correlated with the DNA occupancy of Fli1 and HDAC1, while positively correlating with that of Ets1 and p300. In the functional studies, HDAC1 overexpression magnified the inhibitory effect of Fli1 on the COL1A2 promoter. Moreover, pharmacological blockade of HDAC1 by entinostat enhanced collagen production in dermal fibroblasts. Collectively, these results indicate that under quiescent conditions Fli1 recruits HDAC1/p300 to the COL1A2 promoter and suppresses the expression of the COL1A2 gene by chromatin remodeling through histone deacetylation. TGF-β-dependent phosphorylation of Fli1 at threonine 312 is a critical step regulating the remodeling of the Fli1 transcription repressor complex, leading to transcriptional activation of the COL1A2 gene.
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影响因子：
--
作者：
Hemmatazad, Hossein;Rodrigues, Hanna Maciejewska;Juengel, Astrid
通讯作者：
Juengel, Astrid
影响因子：
--
作者：
Huber, Lars C.;Distler, Joerg H. W.;Juengel, Astrid
通讯作者：
Juengel, Astrid
影响因子：
4.8
作者：
Nakerakanti, Sashidhar S.;Kapanadze, Bagrat;Trojanowska, Maria
通讯作者：
Trojanowska, Maria
DOI：
10.1073/pnas.0700298104
发表时间：
2007-03-13
影响因子：
11.1
作者：
Li, Bin;Samanta, Arabinda;Greene, Mark I.
通讯作者：
Greene, Mark I.
影响因子：
4.8
作者：
Czuwara-Ladykowska, J;Sementchenko, VI;Trojanowska, M
通讯作者：
Trojanowska, M