PMID- 35327967
OWN - NLM
STAT- MEDLINE
DCOM- 20220427
LR  - 20220531
IS  - 2073-4425 (Electronic)
IS  - 2073-4425 (Linking)
VI  - 13
IP  - 3
DP  - 2022 Feb 24
TI  - HNF1A POU Domain Mutations Found in Japanese Liver Cancer Patients Cause 
      Downregulation of HNF4A Promoter Activity with Possible Disruption in 
      Transcription Networks.
LID - 10.3390/genes13030413 [doi]
LID - 413
AB  - Hepatocyte nuclear factor 1A (HNF1A) is the master regulator of liver homeostasis 
      and organogenesis and regulates many aspects of hepatocyte functions. It acts as 
      a tumor suppressor in the liver, evidenced by the increased proliferation in 
      HNF1A knockout (KO) hepatocytes. Hence, we postulated that any loss-of-function 
      variation in the gene structure or composition (mutation) could trigger 
      dysfunction, including disrupted transcriptional networks in liver cells. From 
      the International Cancer Genome Consortium (ICGC) database of cancer genomes, we 
      identified several HNF1A mutations located in the functional Pit-Oct-Unc (POU) 
      domain. In our biochemical analysis, we found that the HNF1A POU-domain mutations 
      Y122C, R229Q and V259F suppressed HNF4A promoter activity and disrupted the 
      binding of HNF1A to its target HNF4A promoter without any effect on the nuclear 
      localization. Our results suggest that the decreased transcriptional activity of 
      HNF1A mutants is due to impaired DNA binding. Through structural simulation 
      analysis, we found that a V259F mutation was likely to affect DNA interaction by 
      inducing large conformational changes in the N-terminal region of HNF1A. The 
      results suggest that POU-domain mutations of HNF1A downregulate HNF4A gene 
      expression. Therefore, to mimic the HNF1A mutation phenotype in transcription 
      networks, we performed siRNA-mediated knockdown (KD) of HNF4A. Through RNA-Seq 
      data analysis for the HNF4A KD, we found 748 differentially expressed genes 
      (DEGs), of which 311 genes were downregulated (e.g., HNF1A, ApoB and SOAT2) and 
      437 genes were upregulated. Kyoto Encyclopedia of Genes and Genomes (KEGG) 
      mapping revealed that the DEGs were involved in several signaling pathways (e.g., 
      lipid and cholesterol metabolic pathways). Protein-protein network analysis 
      suggested that the downregulated genes were related to lipid and cholesterol 
      metabolism pathways, which are implicated in hepatocellular carcinoma (HCC) 
      development. Our study demonstrates that mutations of HNF1A in the POU domain 
      result in the downregulation of HNF1A target genes, including HNF4A, and this may 
      trigger HCC development through the disruption of HNF4A-HNF1A transcriptional 
      networks.
FAU - Haque, Effi
AU  - Haque E
AUID- ORCID: 0000-0002-5176-2318
AD  - Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 
      05-552 Jastrzebiec, Poland.
FAU - Teeli, Aamir Salam
AU  - Teeli AS
AD  - Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 
      05-552 Jastrzebiec, Poland.
FAU - Winiarczyk, Dawid
AU  - Winiarczyk D
AUID- ORCID: 0000-0003-3562-7930
AD  - Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 
      05-552 Jastrzebiec, Poland.
FAU - Taguchi, Masahiko
AU  - Taguchi M
AUID- ORCID: 0000-0001-7154-4644
AD  - Molecular Modeling and Simulation Group, National Institutes for Quantum Science 
      and Technology, Kizugawa 619-0215, Japan.
FAU - Sakuraba, Shun
AU  - Sakuraba S
AUID- ORCID: 0000-0001-5768-2389
AD  - Molecular Modeling and Simulation Group, National Institutes for Quantum Science 
      and Technology, Kizugawa 619-0215, Japan.
FAU - Kono, Hidetoshi
AU  - Kono H
AUID- ORCID: 0000-0001-5729-8707
AD  - Molecular Modeling and Simulation Group, National Institutes for Quantum Science 
      and Technology, Kizugawa 619-0215, Japan.
FAU - Leszczynski, Pawel
AU  - Leszczynski P
AD  - Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 
      05-552 Jastrzebiec, Poland.
FAU - Pierzchala, Mariusz
AU  - Pierzchala M
AD  - Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 
      05-552 Jastrzebiec, Poland.
FAU - Taniguchi, Hiroaki
AU  - Taniguchi H
AD  - Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 
      05-552 Jastrzebiec, Poland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220224
PL  - Switzerland
TA  - Genes (Basel)
JT  - Genes
JID - 101551097
RN  - 0 (HNF1A protein, human)
RN  - 0 (HNF4A protein, human)
RN  - 0 (Hepatocyte Nuclear Factor 1-alpha)
RN  - 0 (Hepatocyte Nuclear Factor 4)
RN  - 0 (Lipids)
SB  - IM
MH  - *Carcinoma, Hepatocellular/genetics
MH  - Down-Regulation
MH  - Gene Regulatory Networks
MH  - Hepatocyte Nuclear Factor 1-alpha/genetics/metabolism
MH  - Hepatocyte Nuclear Factor 4/genetics
MH  - Humans
MH  - Japan
MH  - Lipids
MH  - *Liver Neoplasms/genetics
MH  - Mutation
PMC - PMC8949677
OTO - NOTNLM
OT  - HNF1A
OT  - HNF4A
OT  - POU domain
OT  - hepatocellular carcinoma
OT  - mutation
COIS- The authors declare no conflict of interest.
EDAT- 2022/03/26 06:00
MHDA- 2022/04/28 06:00
PMCR- 2022/02/24
CRDT- 2022/03/25 01:05
PHST- 2022/01/24 00:00 [received]
PHST- 2022/02/18 00:00 [revised]
PHST- 2022/02/19 00:00 [accepted]
PHST- 2022/03/25 01:05 [entrez]
PHST- 2022/03/26 06:00 [pubmed]
PHST- 2022/04/28 06:00 [medline]
PHST- 2022/02/24 00:00 [pmc-release]
AID - genes13030413 [pii]
AID - genes-13-00413 [pii]
AID - 10.3390/genes13030413 [doi]
PST - epublish
SO  - Genes (Basel). 2022 Feb 24;13(3):413. doi: 10.3390/genes13030413.