SOX10, in combination with Sp1, regulates the endothelin receptor type B gene in human melanocyte lineage cells
SOX10, in combination with Sp1, regulates the endothelin receptor type B gene in human melanocyte lineage cells
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DOI：
10.1111/j.1742-4658.2006.05200.x
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发表时间：
2006-04
期刊：
影响因子：
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通讯作者：
S. Yokoyama;K. Takeda;S. Shibahara
中科院分区：
文献类型：
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作者：
S. Yokoyama;K. Takeda;S. Shibahara
瓦登堡综合征 (WS) 是一种听觉色素障碍，表现为感音神经性听力损失以及头发和皮肤异常色素沉着的不同组合。 WS 4 型 (WS4) 是 WS 的一个亚型，其特征是存在无神经节巨结肠，并与编码内皮素 3、B 型内皮素受体 (EDNRB) 或 Sry-box 10 (SOX10) 的基因突变相关。在这里，我们提供了证据，通过 RNA 干扰和染色质免疫沉淀分析判断，SOX10 调节人类黑素细胞谱系细胞中 EDNRB 基因的表达。人黑素细胞优先表达源自传统 EDNRB 启动子的 EDNRB 转录本。 SOX10 通过顺式作用元件、两个富含 CA 的序列和 GC 盒反式激活 EDNRB 启动子。此外，转录因子 Sp1 通过这些顺式作用元件增强了 SOX10 介导的 EDNRB 启动子反式激活的程度。此外，我们还发现，EDNRB 启动子在 HeLa 人宫颈癌细胞中高度甲基化，缺乏 EDNRB 表达，但在黑色素细胞和 HMV-II 黑色素瘤细胞中则不然。用去甲基化试剂 5'-aza-2'-脱氧胞苷处理后，HeLa 细胞中可检测到 EDNRB 的表达，并且在过表达 SOX10 的转化细胞中进一步增强。因此，我们建议SOX10单独或与Sp1组合，调节EDNRB基因的转录，从而确保EDNRB在人黑素细胞中适当的表达水平。
Waardenburg syndrome (WS) is an auditory–pigmentary disorder that exhibits varying combinations of sensorineural hearing loss and abnormal pigmentation of the hair and skin. WS type 4 (WS4), a subtype of WS, is characterized by the presence of the aganglionic megacolon and is associated with mutations in the gene encoding either endothelin 3, endothelin receptor type B (EDNRB), or Sry‐box 10 (SOX10). Here, we provide evidence that SOX10 regulates the expression of EDNRB gene in human melanocyte‐lineage cells, as judged by RNA interference and chromatin immunoprecipitation analyses. Human melanocytes preferentially express the EDNRB transcripts derived from the conventional EDNRB promoter. SOX10 transactivates the EDNRB promoter through the cis‐acting elements, the two CA‐rich sequences and the GC box. Moreover, a transcription factor Sp1 enhances the degree of the SOX10‐mediated transactivation of the EDNRB promoter through these cis‐acting elements. Furthermore, we have shown that the EDNRB promoter is heavily methylated in HeLa human cervical cancer cells, lacking EDNRB expression, but not in melanocytes and HMV‐II melanoma cells. The expression of EDNRB became detectable in HeLa cells after treatment with a demethylating reagent, 5′‐aza‐2′‐deoxycytidine, which was further enhanced in the transformed cells over‐expressing SOX10. We therefore suggest that SOX10, alone or in combination with Sp1, regulates transcription of the EDNRB gene, thereby ensuring appropriate expression level of EDNRB in human melanocytes.