TY - JOUR
T1 - lncRNA Sequencing Reveals Neurodegeneration-Associated FUS Mutations Alter Transcriptional Landscape of iPS Cells That Persists in Motor Neurons
AU - Provasek, Vincent E.
AU - Kodavati, Manohar
AU - Guo, Wenting
AU - Wang, Haibo
AU - Boldogh, Istvan
AU - Van Den Bosch, Ludo
AU - Britz, Gavin
AU - Hegde, Muralidhar L.
N1 - Funding Information:
This research is primarily supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Aging (NIA) of the National Institutes of Health (NIH) under award number RF1NS112719 to M.L.H. Research in the Hegde laboratory is also supported by the NIH awards R01NS088645, R03AG064266, and R01NS094535, as well as the Sherman Foundation Parkinson’s Disease Research Challenge Fund and Houston Methodist Research Institute’s internal funds. M.L.H. acknowledges Everett E. and Randee K. Bernal for their support via the Centenial Endowed Directorship of DNA Repair.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/10/16
Y1 - 2023/10/16
N2 - 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.
AB - 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.
KW - fused-in sarcoma (FUS)
KW - induced pluripotent stem cells (iPSCs)
KW - long non-coding RNAs (lncRNAs)
KW - neurodegenerative disorders
KW - RNA sequencing
KW - RNA, Long Noncoding/genetics
KW - Mutation/genetics
KW - Humans
KW - Induced Pluripotent Stem Cells/metabolism
KW - Amyotrophic Lateral Sclerosis/genetics
KW - Motor Neurons/metabolism
KW - RNA-Binding Protein FUS/genetics
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U2 - 10.3390/cells12202461
DO - 10.3390/cells12202461
M3 - Article
C2 - 37887305
AN - SCOPUS:85175019729
SN - 2073-4409
VL - 12
JO - Cells
JF - Cells
IS - 20
M1 - 2461
ER -