lncRNA Sequencing Reveals Neurodegeneration-Associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists in Motor Neurons

Vincent E. Provasek, Manohar Kodavati, Wenting Guo, Haibo Wang, Istvan Boldogh, Ludo Van Den Bosch, Gavin Britz, Muralidhar L. Hegde

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Fused-in sarcoma (FUS) gene mutations have been implicated in amyotrophic lateral sclerosis (ALS). This study aimed to investigate the impact of FUS mutations (R521H and P525L) on the transcriptome of induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs). Using RNA sequencing (RNA Seq), we characterized differentially expressed genes (DEGs) and differentially expressed lncRNAs (DELs) and subsequently predicted lncRNA–mRNA target pairs (TAR pairs). Our results show that FUS mutations significantly altered the expression profiles of mRNAs and lncRNAs in iPSCs. Using this large dataset, we identified and verified six key differentially regulated TAR pairs in iPSCs that were also altered in iMNs. These target transcripts included: GPR149, NR4A, LMO3, SLC15A4, ZNF404, and CRACD. These findings indicated that selected mutant FUS-induced transcriptional alterations persist from iPSCs into differentiated iMNs. Functional enrichment analyses of DEGs indicated pathways associated with neuronal development and carcinogenesis as likely altered by these FUS mutations. Furthermore, ingenuity pathway analysis (IPA) and GO network analysis of lncRNA-targeted mRNAs indicated associations between RNA metabolism, lncRNA regulation, and DNA damage repair. Our findings provide insights into potential molecular mechanisms underlying the pathophysiology of ALS-associated FUS mutations and suggest potential therapeutic targets for the treatment of ALS.

Original languageEnglish (US)
Article number2461
JournalCells
Volume12
Issue number20
DOIs
StatePublished - Oct 16 2023

Keywords

  • fused-in sarcoma (FUS)
  • induced pluripotent stem cells (iPSCs)
  • long non-coding RNAs (lncRNAs)
  • neurodegenerative disorders
  • RNA sequencing
  • RNA, Long Noncoding/genetics
  • Mutation/genetics
  • Humans
  • Induced Pluripotent Stem Cells/metabolism
  • Amyotrophic Lateral Sclerosis/genetics
  • Motor Neurons/metabolism
  • RNA-Binding Protein FUS/genetics

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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