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

ABSTRACT: Hepatocyte nuclear factor 4? (HNF4?) 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-HNF4? and P2-HNF4? during ontogenesis and carcinogenesis are still obscure. Our study validated the previously reported self-stimulation of P1-HNF4? but invalidated the reported synergism between HNF4? and HNF1?. HNF4A-AS1, a long noncoding RNA, is localized between the P2 and P1 promoters of HNF4A. We identified critical roles of P1-HNF4? 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 HNF1? to induce P2-HNF4? but antagonized HNF4? in HNF4A-AS1 expression. Thus, PAX6 may be important in determining ontogenic and carcinogenic changes of P2-HNF4? and HNF4A-AS1 in the pancreas and intestine. We also interrogated transactivation activities on multiple gene targets by multiple known and novel HNF4? mutants identified in patients with maturity onset diabetes of the young 1 (MODY1) and liver cancer. Particularly, HNF4?-D78A and HNF4?-G79S, two mutants found in liver cancer with mutations in DNA-binding domain, displayed highly gene-specific transactivation activities. Interestingly, HNF4?-Q277X, a MODY1 truncation mutant, antagonized the transactivation activities of HNF1? 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 HNF4? in digestive tissues.

SUBMITTER: Guo S 

PROVIDER: S-EPMC7745837 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature