Identification of differentially expressed genes in the brain of Sebastiscus marmoratus in response to tributyltin exposure

Abstract Background Aging and neurodegenerative diseases are typical metabolic-related processes. As a metabolism-related long non-coding RNA, EPB41L4A-AS has been reported to be potentially involved in the development of brain aging and neurodegenerative diseases. In this study, we sought to reveal the mechanisms of EPB41L4A-AS in aging and neurodegenerative diseases. Methods Human hippocampal gene expression profiles downloaded from the Genotype-Tissue Expression database were analyzed to obtain age-stratified differentially expressed genes; a weighted correlation network analysis algorithm was then used to construct a gene co-expression network of these differentially expressed genes to obtain gene clustering modules. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, protein–protein interaction network, and correlation analysis were used to reveal the role of EPB41L4A-AS1. The mechanism was verified using Gene Expression Omnibus dataset GSE5281 and biological experiments (construction of cell lines, Real-time quantitative PCR, Western blot, measurement of ATP and NAD+ levels, nicotinamide riboside treatment, Chromatin Immunoprecipitation) in neurons and glial-derived cells. Results EPB41L4A-AS1 was downregulated in aging and Alzheimer's disease. EPB41L4A-AS1 related genes were found to be enriched in the electron transport chain and NAD+ synthesis pathway. Furthermore, these genes were highly associated with neurodegenerative diseases and positively correlated with EPB41L4A-AS1. In addition, biological experiments proved that the downregulation of EPB41L4A-AS1 could reduce the expression of these genes via histone H3 lysine 27 acetylation, resulting in decreased NAD+ and ATP levels, while EPB41L4A-AS1 overexpression and nicotinamide riboside treatment could restore the NAD+ and ATP levels. Conclusions Downregulation of EPB41L4A-AS1 not only disturbs NAD+ biosynthesis but also affects ATP synthesis. As a result, the high demand for NAD+ and ATP in the brain cannot be met, promoting the development of brain aging and neurodegenerative diseases. However, overexpression of EPB41L4A-AS1 and nicotinamide riboside, a substrate of NAD+ synthesis, can reduce EPB41L4A-AS1 downregulation-mediated decrease of NAD+ and ATP synthesis. Our results provide new perspectives on the mechanisms underlying brain aging and neurodegenerative diseases.

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Proteomic and Transcriptomic Analyses of the Hippocampus and Cortex in SUDEP and High-Risk SUDEP Cases

10.1101/2020.07.27.223446 ◽

2020 ◽

Author(s):

Dominique F. Leitner ◽

James D. Mills ◽

Geoffrey Pires ◽

Arline Faustin ◽

Eleanor Drummond ◽

...

Keyword(s):

High Risk ◽

Differentially Expressed Genes ◽

Molecular Mechanisms ◽

Brain Activity ◽

Brain Regions ◽

Sudden Unexpected Death ◽

Differentially Expressed ◽

Unexpected Death ◽

Protein Coding ◽

The Brain

AbstractSudden unexpected death in epilepsy (SUDEP) is the leading type of epilepsy-related death. Severely depressed brain activity in these cases may impair respiration, arousal, and protective reflexes, occurring as a prolonged postictal generalized EEG suppression (PGES) and resulting in a high-risk for SUDEP. In autopsy hippocampus and cortex, we observed no proteomic differences between SUDEP and epilepsy cases, contrasting our previously reported robust differences between epilepsy and controls. Transcriptomics in hippocampus and cortex from surgical epilepsy cases segregated by PGES identified 55 differentially expressed genes (37 protein-coding, 15 lncRNAs, three pending) in hippocampus. Overall, the SUDEP proteome and high-risk SUDEP transcriptome largely reflected other epilepsy cases in the brain regions analyzed, consistent with diverse epilepsy syndromes and comorbidities associated with SUDEP. Thus, studies with larger cohorts and different epilepsy syndromes, as well as additional anatomic regions may identify molecular mechanisms of SUDEP.

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The Type 3 Deiodinase Is a Critical Modulator of Thyroid Hormone Sensitivity in the Fetal Brain

Frontiers in Neuroscience ◽

10.3389/fnins.2021.703730 ◽

2021 ◽

Vol 15 ◽

Author(s):

Maria Elena Martinez ◽

Arturo Hernandez

Keyword(s):

Differential Expression ◽

Rna Sequencing ◽

Differentially Expressed Genes ◽

Fetal Brain ◽

Axonal Guidance ◽

Late Gestation ◽

Differentially Expressed ◽

Pathway Analyses ◽

Type 3 ◽

The Brain

Thyroid hormones (TH) are critical for the development and function of the central nervous system (CNS). Although their effects on the rodent brain peak within 2–3 weeks postnatally, the fetal brain has been found largely insensitive to exogenously administrated TH. To address this issue, here we examined gene expression in brains from mouse fetuses deficient in the type 3 deiodinase (DIO3), the selenoenzyme responsible for clearing TH. At embryonic day E18.5 qPCR determinations indicated a marked increase in the mRNA expression of T3-responsive genes Klf9 and Nrgn. The increased expression of these genes was confirmed by in situ hydridization in multiple areas of the cortex and in the striatum. RNA sequencing revealed 246 genes differentially expressed (70% up-regulated) in the brain of E18.5 Dio3−/− male fetuses. Differential expression of 13 of these genes was confirmed in an extended set of samples that included females. Pathway analyses of differentially expressed genes indicated enrichment in glycolysis and signaling related to axonal guidance, synaptogenesis and hypoxia inducible factor alpha. Additional RNA sequencing identified 588 genes differentially expressed (35% up-regulated) in the brain of E13.5 Dio3−/− male fetuses. Differential expression of 13 of these genes, including Klf9, Hr, and Mgp, was confirmed in an extended set of samples including females. Although pathway analyses of differentially expressed genes at E13.5 also revealed significant enrichment in axonal guidance and synaptogenesis signaling, top enrichment was found for functions related to the cell cycle, aryl hydrocarbon receptor signaling, PCP and kinetochore metaphase signaling pathways and mitotic roles of polo-like kinase. Differential expression at E13.5 was confirmed by qPCR for additional genes related to collagen and extracellular matrix and for selected transcription factors. Overall, our results demonstrate that the rodent fetal brain is sensitive to TH as early as E13.5 of gestational age, and suggest that TH distinctly affects brain developmental programs in early and late gestation. We conclude that DIO3 function is critical to ensure an adequate timing for TH action in the developing brain and is probably the main factor underlying the lack of effects on the fetal brain observed in previous studies after TH administration.

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