Haque, E. | bioRxiv Science

bioRxiv2025

The HNF4A Q164X Mutation Impairs Transcriptional Activation in Vitro but Its Heterozygosity Suppresses Liver Tumorigenesis in Vivo

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.

cancer biology↗

bioRxiv2024

Frame-shift mutation of InCO might cause early flowering of Japanese morning glory and might have contributed to northward expansion

Japanese morning glory (Ipomoea nil), a short day plant, has been used for studying flowering times. Here, quantitative trait loci (QTL) analysis for days from sowing to flowering (DTF) of F2 between I. nil var. Tokyo Kokei Standard (TKS) and I. hederacea line var. Q65, an early flowering variety, revealed four QTLs: QTL Ipomoea Flowering 1-4 (qIF1-4). The position of qIF3, which had the most significant effect among the four QTLs, corresponds with that of I. nil (or I. hederacea) CONSTANS (InCO/IhCO) in the linkage map. There is a single-base In/Del in the coding sequence of InCO/IhCO. The single-base deletion (SBD) causes a frame-shift mutation and loss of function in TKS allele (inco-1). I. nil accessions bearing inco-1 tend to flower early, similarly to rice varieties bearing the loss of function allele of CO ortholog, hd1. Consequently, inco-1 was inferred to reduce DTF. This inferred effect of inco-1 corresponds with the effect of the TKS allele of qIF3. Because inco-1 is found exclusively in Asian accessions, the SBD in inco-1 might have played an important role in the expansion of Japanese morning glories, originally native to the tropical regions of the Americas, into temperate Asia.

plant biology↗