Integrated mRNA-seq and miRNA-seq analysis reveals key transcription factors of HNF4α and KLF4 in ADPKD.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 0372516 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1090-2104 (Electronic) Linking ISSN: 0006291X NLM ISO Abbreviation: Biochem Biophys Res Commun Subsets: MEDLINE
    • Publication Information:
      Publication: <2002- >: San Diego, CA : Elsevier
      Original Publication: New York, Academic Press.
    • Subject Terms:
      Hepatocyte Nuclear Factor 4*/genetics ; Hepatocyte Nuclear Factor 4*/metabolism ; Kruppel-Like Factor 4*/metabolism ; MicroRNAs*/genetics ; MicroRNAs*/metabolism ; Kruppel-Like Transcription Factors*/genetics ; Kruppel-Like Transcription Factors*/metabolism ; Polycystic Kidney, Autosomal Dominant*/genetics ; Polycystic Kidney, Autosomal Dominant*/metabolism ; Polycystic Kidney, Autosomal Dominant*/pathology ; RNA, Messenger*/genetics ; RNA, Messenger*/metabolism; Animals ; Humans ; Mice ; Mice, Inbred C57BL ; Gene Expression Profiling ; Kidney/metabolism ; Kidney/pathology ; RNA-Seq ; Gene Expression Regulation ; Male
    • Abstract:
      Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent genetic disorder affecting the kidneys. Understanding epigenetic regulatory mechanisms and the role of microRNAs (miRNAs) is crucial for developing therapeutic interventions. Two mRNA datasets (GSE7869 and GSE35831) and miRNA expression data (GSE133530) from ADPKD patients were used to find differentially expressed genes (DEGs) and differentially expressed miRNAs (DEMs), with a focus on genes regulated by hub transcription factors (TFs) and their target genes. The expression of hub TFs was validated in human kidneys and animal models through Western Blot (WB) and RT-PCR analysis. The location of the hub TF proteins in kidney cells was observed by a laser confocal microscope. A total of 2037 DEGs were identified. DEM analysis resulted in 59 up-regulated and 107 down-regulated miRNAs. Predicted target DEGs of DEMs indicated two top dysregulated TFs: hepatocyte nuclear factor 4 alpha (HNF4α) and Kruppel-like factor 4 (KLF4). RT-PCR, WB, and immunochemistry results showed that mRNA and protein levels of HNF4α were significantly decreased while KLF4 levels were significantly up-regulated in human ADPKD kidneys and Pkd1 conditional knockout mice compared with normal controls. Laser confocal microscopy revealed that KLF4 was mainly located in the cytoplasm while HNF4α was in the nucleus. Functional enrichment analysis indicated that genes regulated by HNF4α were mainly associated with metabolic pathways, while KLF4-regulated genes were linked to kidney development. Drug response prediction analysis revealed potential drug candidates for ADPKD treatment, including BI-2536, Sepantronium, and AZD5582. This integrated analysis provides new epigenetic insights into the complex miRNA-TF-mRNA network in ADPKD and identifies HNF4α and KLF4 as key TFs. These findings offer valuable resources for further research and potential drug development for ADPKD.
      Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Cheng Xue reports was provided by Shanghai Changzheng Hospital. Cheng Xue reports a relationship with Shanghai Changzheng Hospital that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: Autosomal dominant polycystic kidney disease; Bioinformatics; Kruppel-like factor 4; Polycystic kidney disease; Transcription factor; hepatocyte nuclear factor 4 alpha; microRNA
    • Accession Number:
      0 (Hepatocyte Nuclear Factor 4)
      0 (Kruppel-Like Factor 4)
      0 (KLF4 protein, human)
      0 (MicroRNAs)
      0 (Kruppel-Like Transcription Factors)
      0 (Klf4 protein, mouse)
      0 (RNA, Messenger)
      0 (HNF4A protein, human)
    • Publication Date:
      Date Created: 20241021 Date Completed: 20241104 Latest Revision: 20241104
    • Publication Date:
      20241104
    • Accession Number:
      10.1016/j.bbrc.2024.150848
    • Accession Number:
      39432926