Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α

Abstract

Hepatocyte nuclear factor 4α (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-HNF4α 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 noncoding RNA, is localized between the P2 and P1 promoters of HNF4A. We identified critical roles of P1-HNF4α in regulating the expression of HNF4A-AS1 and its mouse ortholog Hnf4a-os. Paired box 6 (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 young 1 (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 farnesoid X receptor, 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.

RETRACTED ARTICLE: HNF4A-AS1/hnRNPU/CTCF axis as a therapeutic target for aerobic glycolysis and neuroblastoma progression

“…In this study, HNF4A-AS1 was identified as a lncRNA upregulated in NB tissues and cell lines. Previous studies indicate that HNF4A-AS1 participates in mucosal injury in Crohn's disease [51], and serves as a HNF4A target gene in hepatocellular carcinoma cells [52]. Our evidence indicated that HNF4A-AS1 facilitated the expression of HNF4A at transcriptional level, and tumor promoting functions of HNF4A-AS1 were mediated, at least in part, through interacting with hnRNPU protein.…”

The Roles of Long Noncoding RNAs HNF1α-AS1 and HNF4α-AS1 in Drug Metabolism and Human Diseases

“…Guo and Lu reported that the expression of HNF4α-AS1 was strongly activated by P1-HNF4α, which is predominantly produced in adult liver, but not P2-HNF4α, which is prevalent in fetal liver, pancreas, and liver/colon cancer. Therefore, HNF4α-AS1 might be a biomarker for P1-HNF4α expression and might be involved in the functional regulation of the liver-specific P1-HNF4α [63]. The knockdown of HNF4α also showed to repress the expression of HNF4α-AS1 in HepaRG cells, which further validated the idea the HNF4α-AS1 was regulated by HNF4α [60].…”

Control of Cell Identity by the Nuclear Receptor HNF4 in Organ Pathophysiology

“…In human colon tumors, P1-driven HNF4A is either lost or localized in the cytoplasm due to an isoform-specific phosphorylation of HNF4A by SRC tyrosine kinase affecting protein stability, nuclear localization, and transactivation function of P1-driven, but not P2-driven, isoforms [ 133 ]. In contrast, P2-driven HNF4A is induced in colon cancer though combined actions of Paired Box 6 (PAX6) and HNF1A [ 177 ]. In line with the P1:P2 ratio playing a key role in the pathophysiology of colon cancer, tumor load and size were increased in mice which could only produce P2-driven HNF4A isoforms in a model of colitis-associated colon cancer, while restricted expression of P1-driven isoforms and led to fewer and smaller tumors [ 32 ].…”