The Gene Coexpression Analysis Identifies Functional Modules Dynamically Changed After Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is a major cause of morbidity and mortality, both in adult and pediatric populations. However, the dynamic changes of gene expression profiles following TBI have not been fully understood. In this study, we identified the differentially expressed genes (DEGs) following TBI. Remarkably, Serpina3n, Asf1b, Folr1, LOC100366216, Clec12a, Olr1, Timp1, Hspb1, Lcn2, and Spp1 were identified as the top 10 with the highest statistical significance. The weighted gene coexpression analysis (WGCNA) identified 12 functional modules from the DEGs, which showed specific expression patterns over time and were characterized by enrichment analysis. Specifically, the black and turquoise modules were mainly involved in energy metabolism and protein translation. The green yellow and yellow modules including Hmox1, Mif, Anxa2, Timp1, Gfap, Cd9, Gja1, Pdpn, and Gpx1 were related to response to wounding, indicating that expression of these genes such as Hmox1, Anxa2, and Timp1 could protect the brains from brain injury. The green yellow module highlighted genes involved in microglial cell activation such as Tyrobp, Cx3cr1, Grn, Trem2, C1qa, and Aif1, suggesting that these genes were responsible for the inflammatory response caused by TBI. The upregulation of these genes has been validated in an independent dataset. These results indicated that the key genes in microglia cell activation may serve as a promising therapeutic target for TBI. In summary, the present study provided a full view of the dynamic gene expression changes following TBI.

Transcriptional Pathology Evolves over Time in Rat Hippocampus after Lateral Fluid Percussion Traumatic Brain Injury

“…Transcriptomics studies have consistently identified major DE signatures across various TBI models, 8 , 47 , 50 , 52–58 and the limited number featuring time-course designs reveal dynamic changes across periods from the hours post-injury to months and even years later. 13 , 59–62 Our results support a previously proposed mechanistic model where surviving neurons activate a transcriptomic signature of cellular reprogramming, development, and regeneration in the aftermath of injury, 53 with relevant terms enriched here in upregulated modules ii and iv. Our findings are also in line with a study that used NanoString to profile candidate genes, finding differences in trajectories of sets of immune and inflammation genes, as well as decreased and shorter persistence of downregulation signatures post-TBI.…”

“…A recent microarray study included the same two time points as used here and found similar time-dependent inflammation signatures. 13 , 59 Our results are generally aligned with findings from this study, though our methods are anchored on DE changes rather than covariance and are thus by transcriptional pathology. Further, by integrating expression and H3K4me3 ChIP-seq in our comparison, we identified underlying epigenetic activation and repression of differentially expressed loci, as describe below.…”

Potential Progression Mechanism and Key Genes in Early Stage of mTBI

“…The complement system is a biochemical pathway involved in both innate and adaptive immune responses and has four main functions: lysis of microorganisms, promotion of phagocytosis, triggering inflammation, and immune clearance [ 25 , 26 ]. The activation of C3 can trigger a continuous degradation mechanism to activate microglia and astrocytes, reduce the density of dendritic cells and synapses, and inhibit the migration of neuroblast cells, which leads to neuron loss after several weeks of TBI [ 27 , 28 ]. The upregulation of C3 can promote the progression of the neurodegenerative diseases, and previous studies have shown that C3 in turn interacts with the C3aR neurons and microglia to mediate β -amyloid pathology and neuroinflammation in AD mouse models.…”

“…e complement system is a biochemical pathway involved in both innate and adaptive immune responses and has four main functions: lysis of microorganisms, promotion of phagocytosis, triggering in ammation, and immune clearance [25,26]. e activation of C3 can trigger a continuous degradation mechanism to activate microglia and astrocytes, reduce the density of dendritic cells and synapses, and inhibit the migration of neuroblast cells, which leads to neuron loss after several weeks of TBI [27,28].…”

The interaction between ASF1B and TLK1 promotes the malignant progression of low-grade glioma

“…ASF1B suppression enhanced the apoptotic ability of prostate cancer cells by inactivating PI3K/Akt pathway [ 11 ]. In addition, gene expression profiles showed a significant increase in ASF1B expression following traumatic brain injury [ 12 ]. However, the influences of ASF1B on LGG have not been uncovered.…”