Conjunction of potential G-quadruplex and adjacent cis-elements in the 5' UTR of hepatocyte nuclear factor 4-alpha strongly inhibit protein expression.
Conjunction of potential G-quadruplex and adjacent cis-elements in the 5' UTR of hepatocyte nuclear factor 4-alpha strongly inhibit protein expression.
复制标题
DOI：
10.1038/s41598-017-17629-y
复制
发表时间：
2017-12-12
影响因子：
4.6
通讯作者：
Lu H
中科院分区：
文献类型：
--
作者：
Guo S;Lu H
肝细胞核因子4-α（HNF 4 α）是一种公认的肝脏发育和功能的主要调节因子。我们在体外鉴定了P1-HNF4A（成人肝脏中主要的HNF4 α亚型）5 ′ UTR中存在稳定的二级结构，G-四链体（G4）。我们的数据表明，G4和5 ′ UTR内邻近的推定蛋白结合位点的合作是必要的，足以介导强翻译抑制。这得到了5 ′ UTR缺失/突变和5 ′ UTR中两个天然调控单核苷酸多态性分析的支持。另外的结果表明，其他肝脏富集的转录因子的5 ′ UTR中的G4基序也抑制蛋白质表达。此外，G4配体pyridostatin特异性地增强P1-HNF4A-5 ′ UTR的翻译抑制作用。总之，本研究首次在体外证明了G4在人P1-HNF 4A-5 ′ UTR中的存在，并建立了一种新的通过G4与潜在的RNA结合蛋白（RBP）相互作用来强抑制蛋白翻译的工作模型。在肝脏发育和癌变过程中，RBP可能通过与5 ′ UTR中G4基序的相互作用抑制肿瘤抑制因子HNF 4 α的蛋白表达，从而促进细胞增殖。
Hepatocyte nuclear factor 4-alpha (HNF4α) is a well established master regulator of liver development and function. We identified the in vitro presence of a stable secondary structure, G-quadruplex (G4) in the 5′ UTR of P1-HNF4A, the predominant HNF4α isoform(s) in adult liver. Our data suggest that the cooperation of G4 and the adjacent putative protein-binding sites within the 5′ UTR was necessary and sufficient to mediate a strong translational repression. This was supported by analysis of deleted/mutated 5′UTRs and two native regulatory single-nucleotide polymorphisms in the 5′UTR. Additional results indicated that G4 motifs in the 5′ UTRs of other liver-enriched transcription factors also inhibited protein expression. Moreover, pyridostatin, a G4 ligand, specifically potentiated the translational suppressing effect of P1-HNF4A-5′ UTR. In summary, the present study provides the first evidence of the presence of G4 in human P1-HNF4A-5′ UTR in vitro, and establishes a novel working model of strong inhibition of protein translation via interactions of G4 with potential RNA-binding proteins (RBPs). The protein expression of the tumor suppressor HNF4α may be inhibited by interactions of RBPs with the G4 motif in the 5′ UTR to promote cell proliferation during liver development and carcinogenesis.
登录
查看更多内容
影响因子：
14.9
作者：
Gomez D;Guédin A;Mergny JL;Salles B;Riou JF;Teulade-Fichou MP;Calsou P
通讯作者：
Calsou P
影响因子：
14.9
作者：
Bugaut A;Balasubramanian S
通讯作者：
Balasubramanian S
影响因子：
14.9
作者：
Halder K;Wieland M;Hartig JS
通讯作者：
Hartig JS
影响因子：
5.3
作者：
Hayhurst, GP;Lee, YH;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
影响因子：
11.4
作者：
BUCK, M;TURLER, H;CHOJKIER, M
通讯作者：
CHOJKIER, M