scholarly journals Pseudogene RPL32P3 regulates the blood–tumor barrier permeability via the YBX2/HNF4G axis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ye Ding ◽  
Xiaobai Liu ◽  
Chunqing Yang ◽  
Xuelei Ruan ◽  
Di Wang ◽  
...  
Keyword(s):  
Glioma Cells ◽  
Underlying Mechanism ◽  
Comprehensive Treatment ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Tumor Tissues ◽  
Lysine Methyltransferase ◽  
Hepatocyte Nuclear Factor 4 ◽  
Related Proteins ◽  
Tumor Drugs

AbstractThe existence of the blood–tumor barrier (BTB) severely hinders the transport of anti-tumor drugs to brain tumor tissues. Selectively opening BTB is of great significance to improve the chemotherapy effect of glioma. Pseudogenes have been recognized as important regulators in various biologic processes. In this study, we identified that ribosomal protein L32 pseudogene 3 (RPL32P3) was highly expressed in glioma-exposed endothelial cells (GECs). Knockdown of RPL32P3 decreased the expression of tight junction-related proteins (TJPs) and increased BTB permeability. Subsequent analysis of the underlying mechanism indicated that RPL32P3 recruited lysine methyltransferase 2 A (KMT2A) to the Y-box binding protein 2 (YBX2) promoter region and mediated H3K4me3 to promote YBX2 transcription. Highly expressed YBX2 bound and stabilized hepatocyte nuclear factor 4 gamma (HNF4G) mRNA. Highly expressed HNF4G directly bound to the promoters of TJPs ZO-1, occludin and claudin-5 to promote their transcriptional activities and regulated BTB permeability. The simultaneous knockdown of RPL32P3, YBX2, and HNF4G combined with doxorubicin (DOX) increased the apoptosis of glioma cells. In conclusion, the current study indicated that RPL32P3 knockdown increased BTB permeability through the YBX2/HNF4G pathway. These findings may provide new targets for the comprehensive treatment of glioma.

scholarly journals Transcriptomically Revealed Oligo-Fucoidan Enhances the Immune System and Protects Hepatocytes via the ASGPR/STAT3/HNF4A Axis

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 898 ◽  
Author(s):  
Chun-Chia Cheng ◽  
Wan-Yu Yang ◽  
Ming-Chen Hsiao ◽  
Kuan-Hao Lin ◽  
Hao-Wei Lee ◽  
...  
Keyword(s):  
Immune System ◽  
Brown Seaweed ◽  
Underlying Mechanism ◽  
Sulfated Polysaccharide ◽  
Driver Gene ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Hepatocyte Nuclear Factor 4

Oligo-fucoidan, a sulfated polysaccharide extracted from brown seaweed, exhibits anti-inflammatory and anti-tumor effects. However, the knowledge concerning the detailed mechanism of oligo-fucoidan on liver cells is obscure. In this study, we investigate the effect of oligo-fucoidan in normal hepatocytes by transcriptomic analysis. Using an oligo-fucoidan oral gavage in wild-type adult zebrafish, we find that oligo-fucoidan pretreatment enhances the immune system and anti-viral genes in hepatocytes. Oligo-fucoidan pretreatment also decreases the expression of lipogenic enzymes and liver fibrosis genes. Using pathway analysis, we identify hepatocyte nuclear factor 4 alpha (HNF4A) to be the potential driver gene. We further investigate whether hepatocyte nuclear factor 4 alpha (HNF4A) could be induced by oligo-fucoidan and the underlying mechanism. Therefore, a normal hepatocyte clone 9 cell as an in vitro model was used. We demonstrate that oligo-fucoidan increases cell viability, Cyp3a4 activity, and Hnf4a expression in clone 9 cells. We further demonstrate that oligo-fucoidan might bind to asialoglycoprotein receptors (ASGPR) in normal hepatocytes through both in vitro and in vivo competition assays. This binding, consequently activating the signal transducer and activator of transcription 3 (STAT3), increases the expression of the P1 isoform of HNF4A. According to our data, we suggest that oligo-fucoidan not only enhances the gene expression associated with anti-viral ability and immunity, but also increases P1-HNF4A levels through ASGPR/STAT3 axis, resulting in protecting hepatocytes.

scholarly journals A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young

Diabetologia ◽  
1997 ◽  
Vol 40 (7) ◽  
pp. 859-862 ◽  
Author(s):  
M. P. Bulman ◽  
M. J. Dronsfield ◽  
T. Frayling ◽  
M. Appleton ◽  
S. C. Bain ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Nuclear Factor ◽  
Maturity Onset Diabetes ◽  
Hepatocyte Nuclear Factor ◽  
Onset Diabetes ◽  
Hepatocyte Nuclear Factor 4 ◽  
Alpha Gene

Tissue-specific regulation of mouse hepatocyte nuclear factor 4 expression

1994 ◽  
Vol 14 (11) ◽  
pp. 7276-7284
Author(s):  
W Zhong ◽  
J Mirkovitch ◽  
J E Darnell
Keyword(s):  
Transcription Factor ◽  
Transgenic Mice ◽  
Transient Transfection ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Distal Enhancer ◽  
Specific Expression ◽  
Tissue Specific ◽  
Hypersensitive Sites ◽  
Hepatocyte Nuclear Factor 4

Hepatocyte nuclear factor 4 (HNF-4) is a liver-enriched transcription factor and a member of the steroid hormone receptor superfamily. HNF-4 is required for the hepatoma-specific expression of HNF-1 alpha, another liver-enriched transcription factor, suggesting the early participation of HNF-4 in development. To prepare for further study of HNF-4 in development, the tissue-specific expression of the mouse HNF-4 gene was studied by analyzing the promoter region for required DNA elements. DNase-hypersensitive sites in the gene in liver and kidney tissues were found in regions both distal and proximal to the RNA start that were absent in tissues in which HNF-4 expression did not occur. By use of reporter constructs in transient-transfection assays and with transgenic mice, a region sufficient to drive liver-specific expression of HNF-4 was identified. While an HNF-1 binding site between bp -98 and -68 played an important role in the hepatoma-specific promoter activity of HNF-4 in transient-transfection assays, it was not sufficient for the liver-specific expression of a reporter gene in transgenic mice. Distal enhancer elements indicated by the presence of DNase I-hypersensitive sites at kb -5.5 and -6.5, while not functional in transient-transfection assays, were required for the correct expression of the mouse HNF-4 gene in animals.

Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells

1992 ◽  
Vol 12 (4) ◽  
pp. 1708-1718
Author(s):  
M Mietus-Snyder ◽  
F M Sladek ◽  
G S Ginsburg ◽  
C F Kuo ◽  
J A Ladias ◽  
...  
Keyword(s):  
Gene Expression ◽  
Regulatory Protein ◽  
Lipid Binding ◽  
Hepatic Tissue ◽  
Nuclear Factor ◽  
Apolipoprotein Ai ◽  
Hepatocyte Nuclear Factor ◽  
Apolipoprotein Ciii ◽  
Caco2 Cells ◽  
Hepatocyte Nuclear Factor 4

Apolipoprotein CIII (apoCIII), a lipid-binding protein involved in the transport of triglycerides and cholesterol in the plasma, is synthesized primarily in the liver and the intestine. A cis-acting regulatory element, C3P, located at -90 to -66 upstream from the apoCIII gene transcriptional start site (+1), is necessary for maximal expression of the apoCIII gene in human hepatoma (HepG2) and intestinal carcinoma (Caco2) cells. This report shows that three members of the steroid receptor superfamily of transcription factors, hepatocyte nuclear factor 4 (HNF-4), apolipoprotein AI regulatory protein 1 (ARP-1), and Ear3/COUP-TF, act at the C3P site. HNF-4 activates apoCIII gene expression in HepG2 and Caco2 cells, while ARP-1 and Ear3/COUP-TF repress its expression in the same cells. HNF-4 activation is abolished by increasing amounts of ARP-1 or Ear3/COUP-TF, and repression by ARP-1 or Ear3/COUP-TF is alleviated by increasing amounts of HNF-4. HNF-4 and ARP-1 bind with similar affinities to the C3P site, suggesting that their opposing transcriptional effects may be mediated by direct competition for DNA binding. HNF-4 and ARP-1 mRNAs are present within the same cells in the liver and intestine, and protein extracts from hepatic tissue, HepG2, and Caco2 cells contain significantly more HNF-4 than ARP-1 or Ear3/COUP-TF binding activities. These findings suggest that the transcription of the apoCIII gene in vivo is dependent, at least in part, upon the intracellular balance of these positive and negative regulatory factors.

scholarly journals A Novel -192c/g Mutation in the Proximal P2 Promoter of the Hepatocyte Nuclear Factor-4  Gene (HNF4A) Associates With Late-Onset Diabetes

Diabetes ◽  
2006 ◽  
Vol 55 (6) ◽  
pp. 1869-1873 ◽  
Author(s):  
J. Ek ◽  
S. P. Hansen ◽  
M. Lajer ◽  
C. Nicot ◽  
T. W. Boesgaard ◽  
...  
Keyword(s):  
Late Onset ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Onset Diabetes ◽  
P2 Promoter ◽  
Hepatocyte Nuclear Factor 4
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