Granulocyte Colony‐Stimulating Factor Alleviates Bacterial‐Induced Neuronal Apoptotic Damage in the Neonatal Rat Brain through Epigenetic Histone Modification

Abstract

Bacterial meningitis during the perinatal period may cause long-term neurological deficits. The study investigated whether bacterial lipopolysaccharide (LPS) derived from E. coli. led to neuronal apoptosis with an impaired performance of long-term cognitive function involving the activation of histone modification in the TNF-α gene promoter. Further, we looked into the therapeutic efficacy of granulocyte colony-stimulating factor (G-CSF) in a neonatal brain suffering from perinatal bacterial meningitis. We applied the following research techniques: neurobehavioral tasks, confocal laser microscopy, chromatin immunoprecipitation, and Western blotting. At postnatal day 10, the animals were subjected to LPS and/or G-CSF. The target brain tissues were then collected at P17. Some animals (P45) were studied using neurobehavioral tasks. The LPS-injected group revealed significantly increased expression of NF-κB phosphorylation and trimethylated H3K4 in the TNFA gene promoter locus. Furthermore, the caspase-3, neuronal apoptosis expression, and an impaired performance in cognitive functions were also found in our study. Such deleterious outcomes described above were markedly alleviated by G-CSF therapy. This study suggests that selective therapeutic action sites of G-CSF through epigenetic regulation in the TNFA gene promoter locus may exert a potentially beneficial role for the neonatal brain suffering from perinatal bacterial-induced meningitis.

Mixed Lineage Leukemia 1 Promoted Neuron Apoptosis in Ischemic Penumbra via Regulating ASK-1/TNF-α Complex

“…Recently, aberrant epigenetic histone modification was found to be involved in neuron apoptosis. As an active histone modification, the H3K4me3 level had been proven to be upregulated in the promoter region of some specific genes during the neuronal apoptotic process (Yung et al, 2018 ). MLL1 is the main HMT that catalyzes the methylation of H3K4 site (Yang and Ernst, 2017 ).…”

“…To prevent TNF-α-induced apoptosis, serine–threonine kinase receptor-associated protein (STRAP) and 14-3-3 proteins interact with ASK-1 to disrupt associations between TNF receptor-associated factor 2 and ASK-1 upon TNF-α stimulation (Hatai et al, 2000 ; Han et al, 2015 ). In recent years, the aberrant histone methylation was suggested to be associated with neuron cell apoptosis (Zhoa et al, 2016 ; Yung et al, 2018 ). Histone methylation can promote or inhibit the transcription of methylation sites, and lysine (K) methylation of histone is a research hotspot in recent years (Alam et al, 2015 ; Kim et al, 2017 ).…”

Dextromethorphan Suppresses Lipopolysaccharide-Induced Epigenetic Histone Regulation in the Tumor Necrosis Factor-α Expression in Primary Rat Microglia

“…Chromatin immunoprecipitation assay was achieved as previously reported [ 8 ]. Briefly, 5 × 10 5 cells were incubated for 10 minutes at room temperature with 1% formaldehyde, followed by sonication of DNAs and the immunoprecipitation of chromatin overnight with the selective antibody for trimethylated H3K4 (2 μ g for 25 μ g of chromatin; anti-histone H3K4me3 antibody, ChIP Grade; ab8580; Abcam Co.) and then purification with the ChIP kit (ChIP kit number 17-295; Upstate Biotechnology, Lake Placid, NY, USA).…”

“…It has long been known that the epigenetic regulatory mechanisms include DNA methylation, histone modification, and noncoding RNAs. The expression of TNF- α messenger RNA and protein was reported by epigenetic modifications of the TNF- α promoter gene through DNA methylation or chromatin remodeling [ 8 ]. Trimethylation of H3K4 contributes significantly in the initial recruitment of a methyltransferase complex that associates with the P65 protein of the NF- κ B family and mediates dimethylation to trimethylation conversion of histone H3 at K4 [ 9 ].…”

“…The NF- κ B had reported regulated its downstream gene transcription such as TNF- α [ 10 ]. Additionally, our previous reported that bacterial LPS could enhance trimethylation of histone 3 at lysine 4 (H3K4me3) in the TNF- α promoter gene locus associated with neuronal apoptotic damage in the neonatal rat brain [ 8 ]. Furthermore, such a bacterial LPS-induced increase in TNF- α expression caused an activity-dependent neuronal apoptosis in the neonatal cerebral cortex [ 11 , 12 ].…”