The HNF4A Q164X Mutation Impairs Transcriptional Activation in Vitro but Its Heterozygosity Suppresses Liver Tumorigenesis in Vivo
Winiarczyk, D.; Khodadadi, H.; Haque, E.; Poznanski, P.; Sacharczuk, M.; Taniguchi, H.
Show abstract
Hepatocyte nuclear factor 4 alpha (HNF4A) is a master regulator of hepatic differentiation and metabolism. Here, we identify and characterize a truncating Q164X mutation that impairs HNF4A transcriptional activity in vitro and causes embryonic lethality when homozygous. Functional assays revealed that the Q164X protein retains nuclear localization but exhibits severely reduced DNA binding and transcriptional activation. CRISPR-generated Q164X mice showed no viable homozygotes, confirming the essential role of HNF4A in early embryogenesis. Unexpectedly, heterozygous Q164X mutants displayed reduced liver tumorigenesis following diethylnitrosamine and high-fat diet treatment, despite downregulation of HNF4A target genes such as ApoB and Hnf1a. These results suggest that partial HNF4A deficiency may trigger compensatory metabolic networks that protect against carcinogenic stress. Collectively, our study establishes Q164X as a loss-of-function HNF4A mutation with paradoxical tumor-suppressive effects in vivo.
Matching journals
The top 14 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Tagging allows faithful tracing of expression and enhances biochemical detection of Ran Binding Protein 9 in vivo and reveals its interaction with Nucleolin. 94%
- Characterization of regulatory transcriptional mechanisms in hepatocyte lipotoxicity 93%
- Diet-induced rewiring of the Wnt gene regulatory network connects aberrant splicing to fatty liver and liver cancer in DIAMOND mice 93%
Similar papers in this journal
- Characterization of Poldip2 knockout mice: avoiding incorrect gene targeting 91%
- Dimeric prion protein ligand activates Adgrg6 but does not rescue myelinopathy of PrP-deficient mice 91%
- Oncogenic mutation or overexpression of oncogenic KRAS or BRAF is not sufficient to confer oncogene addiction. 91%
Similar papers in this journal
- Dicer1 promotes Aβ clearance via blocking B2 RNA-mediated repression of apolipoprotein E 92%
- DNA methylation mediated downregulation of histone H3 variant H3.3 affects cell proliferation contributing to the development of HCC 91%
- Similar metabolic pathways are affected in both Congenital Myasthenic Syndrome 22 and Prader Willi Syndrome 90%
Similar papers in this journal
- Spatial modeling reveals nuclear phosphorylation and subcellular shuttling of YAP upon drug-induced liver injury 93%
- Transcription regulation of SARS-CoV-2 receptor ACE2 by Sp1: a potential therapeutic target 93%
- Bestrophin-4 relays Hes4 and interacts with Twist1 to suppress epithelial-to-mesenchymal transition in colorectal cancer cells 92%
Similar papers in this journal
- Disrupted Post-Transcriptional Regulation of Gene Expression as A Hallmark of Fatty Liver Progression 93%
- Differential Dynamics and Roles of FKBP51 Isoforms and Their Implications for Targeted Therapies 92%
- Vagus nerve mediated liver-brain axis is a major regulator of the metabolic landscape in the liver 92%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.