Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α.
Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α.
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调控肝细胞核因子4α表达和转录活性的新机制。
DOI：
10.1002/jcb.27407
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发表时间：
2019-01
影响因子：
4
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4α (HNF4α)是消化组织发育和功能的主要调节因子。HNF4A基因使用两个独立的启动子P1和P2，其中P1产物在成人肝脏中占主导地位，而P2产物在胎儿肝脏、胰腺和肝癌/结肠癌中普遍存在。迄今为止，HNF4A的调控机制以及P1和P2-HNF4α在个体发生和癌变过程中的动态开关机制尚不清楚。我们的研究证实了先前报道的P1-HNF4α的自我刺激，但证实了HNF4α和HNF1α之间的协同作用。HNF4A- as1是一种长链非编码RNA，定位于HNF4A的P2和P1启动子之间。我们发现P1-HNF4α在调节HNF4A-AS1及其小鼠同源Hnf4a-os表达中的关键作用。PAX6是胰腺发育的主要调控因子，在结肠癌中过表达，PAX6与HNF1α共同诱导P2-HNF4α表达，而与HNF4α拮抗HNF4A-AS1表达。因此，PAX6可能在确定胰腺和肠道中P2-HNF4α和HNF4A-AS1的致瘤性和致癌性变化中起重要作用。我们还研究了在年轻人成熟型糖尿病（MODY1）和肝癌患者中发现的多种已知和新型HNF4α突变体对多个基因靶点的反活化活性。特别是在肝癌中发现的两个dna结合域突变体HNF4α-D78A和HNF4α-G79S表现出高度的基因特异性转激活活性。有趣的是，MODY1截断突变体HNF4α-Q277X可以拮抗胰岛素分泌的关键调节因子hnf4 α和FXR的转激活活性。综上所述，我们的研究为HNF4α在消化组织中的转录调控和反激活活性提供了新的机制见解。
Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of development and function of digestive tissues. The HNF4A gene uses two separate promoters P1 and P2, with P1 products predominant in adult liver whereas P2 products prevalent in fetal liver, pancreas, and liver/colon cancer. To date, the mechanisms for the regulation of HNF4A and the dynamic switch of P1 and P2-HNF4α during ontogenesis and carcinogenesis are still obscure. Our study validated the previously reported self-stimulation of P1-HNF4α but invalidated the reported synergism between HNF4α and HNF1α. HNF4A-AS1, a long-non-coding RNA, is localized between the P2 and P1 promoter of HNF4A. We identified critical roles of P1-HNF4α in regulating the expression of HNF4A-AS1 and its mouse ortholog Hnf4a-os. PAX6, a master regulator of pancreas development overexpressed in colon cancer, cooperated with HNF1α to induce P2-HNF4α but antagonized HNF4α in HNF4A-AS1 expression. Thus, PAX6 may be important in determining ontogenic and carcinogenic changes of P2-HNF4α and HNF4A-AS1 in the pancreas and intestine. We also interrogated transactivation activities on multiple gene targets by multiple known and novel HNF4α mutants identified in patients with maturity onset diabetes of the young1 (MODY1) and liver cancer. Particularly, HNF4α-D78A and HNF4α-G79S, two mutants found in liver cancer with mutations in DNA-binding domain, displayed highly gene-specific transactivation activities. Interestingly, HNF4α-Q277X, a MODY1 truncation mutant, antagonized the transactivation activities of HNF1α and FXR, key regulators of insulin secretion. Taken together, our study provides novel mechanistic insights regarding the transcriptional regulation and transactivation activity of HNF4α in digestive tissues.
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