Hepatocyte Nuclear Factor 4α Transcriptionally Activates TM4SF5 Through The DR1 Motif
10.16476/j.pibb.2024.0416
- VernacularTitle:肝细胞核因子4A通过DR1基序激活TM4SF5的转录
- Author:
Yi-Ming GUO
1
;
Xiao-Fei ZHANG
1
;
Han FENG
1
;
Li ZHENG
1
Author Information
1. Key Laboratory of RNA Biology, Center for Big Data Research in Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
- Publication Type:Journal Article
- Keywords:
HNF4A;
RNA-seq;
TM4SF5;
DR1 motif;
MODY1
- From:
Progress in Biochemistry and Biophysics
2025;52(5):1241-1251
- CountryChina
- Language:English
-
Abstract:
ObjectiveHepatocyte nuclear factor 4-alpha (HNF4A) is a critical transcription factor in the liver and pancreas. Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1 (MODY1). Notably, MODY1 patients with HNF4A pathogenic mutations exhibit decreased responses to arginine and reduced plasma triglyceride levels, but the mechanisms remain unclear. This study aims to investigate the potential target genes transcriptionally regulated by HNF4A and explore its role in these metabolic pathways. MethodsA stable 293T cell line expressing the HNF1A reporter was overexpressed with HNF4A. RNA sequencing (RNA-seq) was performed to analyze transcriptional differences. Transcription factor binding site prediction was then conducted to identify HNF4A binding motifs in the promoter regions of relevant target genes. ResultsRNA-seq results revealed a significant upregulation of transmembrane 4 L six family member 5 (TM4SF5) mRNA in HNF4A-overexpressing cells. Transcription factor binding predictions suggested the presence of five potential HNF4A binding motifs in the TM4SF5 promoter. Finally, we confirmed that the DR1 site in the -57 to -48 region of the TM4SF5 promoter is the key binding motif for HNF4A. ConclusionThis study identified TM4SF5 as a target gene of HNF4A and determined the key binding motif involved in its regulation. Given the role of TM4SF5 as an arginine sensor in mTOR signaling activation and triglyceride secretion, which closely aligns with phenotypes observed in MODY1 patients, our findings provide novel insights into the possible mechanisms by which HNF4A regulates triglyceride secretion in the liver and arginine-stimulated insulin secretion in the pancreas.
