Time-series analysis of hematopoietic stem cells

Abstract

This study aimed to investigate the molecular mechanisms underlying the aging of hematopoietic stem cells (HSCs). Gene expression profile GSE32719 was downloaded from the Gene Expression Omnibus database, including 14 young, 5 middle, and 8 old HSCs. Differential expression analysis, short time-series expression miner analysis, and weighted co-expression network analysis were conducted to screen for hub genes whose expression changed over time during HSC aging. Subsequently, functional enrichment and multiple regulatory network analyses of the hub genes were performed. A total of 124 intersecting time-dependent differentially expressed and module genes were obtained, which were considered hub genes whose expression changed over time during HSC aging. Hub genes were significantly enriched in pathways such as the Hippo and AMP-activated protein kinase (AMPK) signaling pathways. Moreover, AP-1 Transcription Factor Subunit (FOS) and sirtuin 1 (SIRT1) had higher degrees in the protein-protein interaction network, were regulated by more transcription factors (TFs), such as Sp1 transcription factor (SP1) and BRCA1 DNA repair-associated (BRCA1), in the TF-mRNA-miRNA network, were associated with more diseases in the disease-gene network, and could be targeted by more drugs in the drug-gene network. Furthermore, SIRT1 was targeted by miR-9-5p in the TF-mRNA-miRNA network. Hub genes such as FOS and SIRT1 and key pathways such as the Hippo and AMPK signaling pathways may play crucial roles in HSC aging. Moreover, FOS and SIRT1 were regulated by SP1 and BRCA1, respectively, during HSC aging. Furthermore, miR-9-5p may modulate HSC aging by targeting SIRT1. Thus, FOS and SIRT1 may be potential therapeutic targets for age-related hematopoietic dysfunction.

Figure 1.

(A) Volcano plot and clustering heat map for DEGs in the middle vs young group; (B) Volcano plot and clustering heat map for DEGs in the old vs young group. (C) Clustering of temporal gene expression profiles by short time-series expression miner (STEM) analysis. DEGs = differentially expressed genes.

Figure 2.

(A) Scale independence. (B) Cluster dendrogram.(C) Correlations between modules and phenotypic trait (age). (D) UpSetR plot.

Figure 3.

(A) Gene Ontology (GO) enrichment analysis for hub genes. (B) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for hub genes.

Figure 4.

(A) The protein-protein interaction (PPI) network. (B) The TF-mRNA-miRNA network. TFs = transcription factors.

Figure 5.

(A) The disease-gene network. (B) The drug-gene network.