Bipartite regulation of cellular communication network factor 2 and fibroblast growth factor 1 genes by fibroblast growth factor 1 through histone deacetylase 1 and fork head box protein A1
Bipartite regulation of cellular communication network factor 2 and fibroblast growth factor 1 genes by fibroblast growth factor 1 through histone deacetylase 1 and fork head box protein A1
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DOI：
10.1007/s12079-020-00600-4
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发表时间：
2021-01-04
影响因子：
4.1
通讯作者：
Kubota, Satoshi
中科院分区：
文献类型：
--
作者：
Elseoudi, Abdellatif;Nishida, Takashi;Kubota, Satoshi
成纤维细胞生长因子1（FGF-1）是FGF家族的第一个成员，它诱导成纤维细胞和其他类型的细胞增殖。然而，最近的研究揭示了这种分子的意想不到的功能。我们以前的研究重新定义了这种生长因子作为一种分解代谢分子产生的软骨后代谢损伤。事实上，发现FGF-1抑制细胞通讯网络因子2（CCN 2）的基因表达，该因子保护和再生软骨，通过正反馈调节放大其自身的产生。在本研究中，我们研究了软骨细胞中FGF-1对CCN 2抑制和FGF-1激活的分子机制。组蛋白去乙酰化酶1（HDAC 1）抑制剂丙戊酸可部分抑制人软骨细胞中CCN 2的表达和诱导FGF 1的表达，表明该系统中组蛋白乙酰化参与了染色质重塑。相反，RNA降解分析表明，没有贡献的转录后调节的mRNA稳定性的FGF-1所赋予的效果。怀疑由特定转录因子调节，我们接下来从大型数据集中通过计算机寻找候选者。因此，我们发现叉头盒蛋白A1（FOXA 1）作为与CCN 2和FGF 1基因座结合的转录因子。功能分析表明，FOXA 1沉默显着减弱CCN 2抑制和FGF 1诱导引起的FGF 1。这些发现共同表明，FGF-1的双向调节是通过HDAC的染色质重塑和FOXA 1的转录调节与相反功能的未知转录共激活因子的组合实现的。
Fibroblast growth factor 1 (FGF-1) is the first FGF family member, and it induces proliferation of fibroblasts and other types of the cells. However, recent studies are uncovering unexpected functions of this molecule. Our previous study redefined this growth factor as a catabolic molecule produced in cartilage upon metabolic insult. Indeed, FGF-1 was found to repress the gene expression of cellular communication network factor 2 (CCN2), which protects and regenerates cartilage, amplifying its own production through positive feedback regulation. In the present study, we investigated the molecular mechanism of this bipartite CCN2 repression and FGF1 activation by FGF-1 in chondrocytes. Repression of CCN2 and induction of FGF1 in human chondrocytic cells were both partly abolished by valproic acid, an inhibitor of histone deacetylase 1 (HDAC1), indicating the involvement of chromatin remodeling by histone acetylation in this system. In contrast, RNA degradation analysis suggested no contribution of post-transcriptional regulation of the mRNA stability to the effects conferred by FGF-1. Suspecting a regulation by a specific transcription factor, we next sought a candidate in silico from a large dataset. As a result, we found fork head box protein A1 (FOXA1) as the transcription factor that bound to both CCN2 and FGF1 loci. Functional analysis demonstrated that FOXA1 silencing significantly attenuated the CCN2 repression and FGF1 induction caused by FGF1. These findings collectively indicate that the bipartite regulation by FGF-1 is enabled by the combination of chromatin remodeling by HDACs and transcriptional modulation by FOXA1 with unknown transcriptional coactivators of opposite functionalities.