首页|Transcription Factors HNF1A,HNF4A,and FOXA2 Regulate Hepatic Cell Protein N-Glycosylation

Transcription Factors HNF1A,HNF4A,and FOXA2 Regulate Hepatic Cell Protein N-Glycosylation

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Hepatocyte nuclear factor 1 alpha(HNF1 A),hepatocyte nuclear factor 4 alpha(HNF4A),and forkhead box protein A2(FOXA2)are key transcription factors that regulate a complex gene network in the liver,cre-ating a regulatory transcriptional loop.The Encode and ChIP-Atlas databases identify the recognition sites of these transcription factors in many glycosyltransferase genes.Our in silico analysis of HNF1A,HNF4A,and FOXA2 binding to the ten candidate glyco-genes studied in this work confirms a significant enrich-ment of these transcription factors specifically in the liver.Our previous studies identified HNF1A as a master regulator of fucosylation,glycan branching,and galactosylation of plasma glycoproteins.Here,we aimed to functionally validate the role of the three transcription factors on downstream glyco-gene transcriptional expression and the possible effect on glycan phenotype.We used the state-of-the-art clus-tered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)molecular tool for the downregulation of the HNF1A,HNF4A,and FOXA2 genes in HepG2 cells-a human liver cancer cell line.The results show that the downregulation of all three genes individually and in pairs affects the transcrip-tional activity of many glyco-genes,although downregulation of glyco-genes was not always followed by an unambiguous change in the corresponding glycan structures.The effect is better seen as an overall change in the total HepG2 N-glycome,primarily due to the extension of biantennary glycans.We propose an alternative way to evaluate the N-glycome composition via estimating the overall complexity of the glycome by quantifying the number of monomers in each glycan structure.We also propose a model showing feedback loops with the mutual activation of HNF1A-FOXA2 and HNF4A-FOXA2 affecting glyco-genes and protein glycosylation in HepG2 cells.

Clustered regularly interspaced short palindromic repeats/dead Cas9(CRISPR/dCas9)EpigeneticsHepatocyte nuclear factor 1 alpha(HNF1A)Hepatocyte nuclear factor 4 alpha(HNF4A)Forkhead box protein A2(FOXA2)N-glycosylationHepG2 cells

Vedrana Vi?i? Bo?kor、Nika Foglar、Goran Josipovi?、Marija Klasi?、Ana Vuji?、Branimir Plav?a、Toma Keser、Samira Smajlovi?、Aleksandar Vojta、Vlatka Zoldo?

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Laboratory for Epigenetics,Department of Biology,Faculty of Science,University of Zagreb,Zagreb 10000,Croatia

Genos Glycoscience Research Laboratory,Zagreb 10000,Croatia

Faculty of Pharmacy and Biochemistry,University of Zagreb,Zagreb 10000,Croatia

European Structural and Investment FundedCroatian National Centre of Research Excellence in Personalized Healthcare GrantEuropean Regional Development FundGlycosylation analysis was performed in the Genos Glycoscience Research LaboratoryEuropean Structural and Investment Funded Project of Centre of Competence in Molecular DiagnosticsCroatian National Centre of Research Excellence in Personalized Healthcare Grant

KK.01.2.1.02.0321KK.01.1.1.01.0010KK.01.1.1.04.0085KK.01.2.2.03.0006KK.01.1.1.01.0010

2024

10.1016/j.eng.2023.09.019

工程(英文)

工程(英文)

CSTPCDEI
ISSN：2095-8099
年,卷(期)：2024.32(1)
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