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Genomic Fabric Remodeling in Neurological Disorders
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Genomic Fabric Remodeling in Neurological Disorders

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 12491

Special Issue Editors

Dr. Dumitru A. Iacobas

E-Mail Website
Guest Editor
Personalized Genomics Laboratory, Undergraduate Medical Academy, Prairie View A&M University, Prairie View, TX 77446, USA
Interests: cancer therapy; cancer biomarker; neurogenomics; systems biology; intercellular communication; neurotransmission
Special Issues, Collections and Topics in MDPI journals
Dr. David C. Spray

E-Mail Website
Guest Editor
DP Purpura Department of Neuroscience, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Interests: gap junctions; astrocytes; neuron–glial interactions; peripheral pain mechanisms

Special Issue Information

Dear Colleagues,

Hundreds of millions of people worldwide live with disorders affecting the brain, spinal cord, and peripheral nerves. Although neurological disorders have been intensively studied in humans and animal models, their underlying gene expression patterns (the transcriptomes) are still not fully understood. It has now become clear that the transcriptome is a multidimensional system composed of interacting, partially overlapping genomic fabrics, in which organizational principles are race/strain-, sex-, and age-dependent and can be altered by strong external stimuli.

In this Special Issue, we define the organizational feature of genomic fabrics and their interplay in specialized cells and regions of the nervous system. We aim to provide the reader with updated experimental and theoretical methods to explore, analyze, and interpret gene expression data resulting from RNA sequencing and microarray studies. Contributing papers will present quantification of the genomic fabrics remodeling in several severe neurological diseases and restoration following targeted therapies.

Dr. Dumitru A. Iacobas
Dr. David C. Spray
Guest Editors

Manuscript Submission Information

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Keywords

  • Brain
  • Computational genomics
  • Functional genomics
  • Glia
  • Neurodegeneration
  • Neurons
  • Neurotransmission
  • Peripheral nerves
  • Sex differences
  • Spinal cord

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Published Papers (4 papers)

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21 pages, 3475 KiB  
Article
TWEAKing the Hippocampus: The Effects of TWEAK on the Genomic Fabric of the Hippocampus in a Neuropsychiatric Lupus Mouse Model
by Dumitru A. Iacobas, Jing Wen, Sanda Iacobas, Chaim Putterman and Noa Schwartz
Genes 2021, 12(8), 1172; https://doi.org/10.3390/genes12081172 - 29 Jul 2021
Cited by 6 | Viewed by 2394
Abstract
Neuropsychiatric manifestations of systemic lupus erythematosus (SLE), specifically cognitive dysfunction and mood disorders, are widely prevalent in SLE patients, and yet poorly understood. TNF-like weak inducer of apoptosis (TWEAK) has previously been implicated in the pathogenesis of neuropsychiatric lupus (NPSLE), and we have [...] Read more.
Neuropsychiatric manifestations of systemic lupus erythematosus (SLE), specifically cognitive dysfunction and mood disorders, are widely prevalent in SLE patients, and yet poorly understood. TNF-like weak inducer of apoptosis (TWEAK) has previously been implicated in the pathogenesis of neuropsychiatric lupus (NPSLE), and we have recently shown its effects on the transcriptome of the cortex of the lupus-prone mice model MRL/lpr. As the hippocampus is thought to be an important focus of NPSLE processes, we explored the TWEAK-induced transcriptional changes that occur in the hippocampus, and isolated several genes (Dnajc28, Syne2, transthyretin) and pathways (PI3K-AKT, as well as chemokine-signaling and neurotransmission pathways) that are most differentially affected by TWEAK activation. While the functional roles of these genes and pathways within NPSLE need to be further investigated, an interesting link between neuroinflammation and neurodegeneration appears to emerge, which may prove to be a promising novel direction in NPSLE research. Full article
(This article belongs to the Special Issue Genomic Fabric Remodeling in Neurological Disorders)
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25 pages, 5217 KiB  
Article
Retinal Genomic Fabric Remodeling after Optic Nerve Injury
by Pedro Henrique Victorino, Camila Marra, Dumitru Andrei Iacobas, Sanda Iacobas, David C. Spray, Rafael Linden, Daniel Adesse and Hilda Petrs-Silva
Genes 2021, 12(3), 403; https://doi.org/10.3390/genes12030403 - 11 Mar 2021
Cited by 8 | Viewed by 2888
Abstract
Glaucoma is a multifactorial neurodegenerative disease, characterized by degeneration of the retinal ganglion cells (RGCs). There has been little progress in developing efficient strategies for neuroprotection in glaucoma. We profiled the retina transcriptome of Lister Hooded rats at 2 weeks after optic nerve [...] Read more.
Glaucoma is a multifactorial neurodegenerative disease, characterized by degeneration of the retinal ganglion cells (RGCs). There has been little progress in developing efficient strategies for neuroprotection in glaucoma. We profiled the retina transcriptome of Lister Hooded rats at 2 weeks after optic nerve crush (ONC) and analyzed the data from the genomic fabric paradigm (GFP) to bring additional insights into the molecular mechanisms of the retinal remodeling after induction of RGC degeneration. GFP considers three independent characteristics for the expression of each gene: level, variability, and correlation with each other gene. Thus, the 17,657 quantified genes in our study generated a total of 155,911,310 values to analyze. This represents 8830x more data per condition than a traditional transcriptomic analysis. ONC led to a 57% reduction in RGC numbers as detected by retrograde labeling with 1,1′-dioctadecyl-3,3,3,3′-tetramethylindocarbocyanine perchlorate (DiI). We observed a higher relative expression variability after ONC. Gene expression stability was used as a measure of transcription control and disclosed a robust reduction in the number of very stably expressed genes. Predicted protein–protein interaction (PPI) analysis with STRING revealed axon and neuron projection as mostly decreased processes, consistent with RGC degeneration. Conversely, immune response PPIs were found among upregulated genes. Enrichment analysis showed that complement cascade and Notch signaling pathway, as well as oxidative stress and kit receptor pathway were affected after ONC. To expand our studies of altered molecular pathways, we examined the pairwise coordination of gene expressions within each pathway and within the entire transcriptome using Pearson correlations. ONC increased the number of synergistically coordinated pairs of genes and the number of similar profiles mainly in complement cascade and Notch signaling pathway. This deep bioinformatic study provided novel insights beyond the regulation of individual gene expression and disclosed changes in the control of expression of complement cascade and Notch signaling functional pathways that may be relevant for both RGC degeneration and remodeling of the retinal tissue after ONC. Full article
(This article belongs to the Special Issue Genomic Fabric Remodeling in Neurological Disorders)
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22 pages, 3749 KiB  
Article
Remodeling of Neurotransmission, Chemokine, and PI3K-AKT Signaling Genomic Fabrics in Neuropsychiatric Systemic Lupus Erythematosus
by Dumitru Iacobas, Jing Wen, Sanda Iacobas, Noa Schwartz and Chaim Putterman
Genes 2021, 12(2), 251; https://doi.org/10.3390/genes12020251 - 10 Feb 2021
Cited by 10 | Viewed by 2600
Abstract
Cognitive dysfunction and mood changes are prevalent and especially taxing issues for patients with systemic lupus erythematosus (SLE). Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its cognate receptor Fn14 have been shown to play an important role in neurocognitive dysfunction [...] Read more.
Cognitive dysfunction and mood changes are prevalent and especially taxing issues for patients with systemic lupus erythematosus (SLE). Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its cognate receptor Fn14 have been shown to play an important role in neurocognitive dysfunction in murine lupus. We profiled and compared gene expression in the cortices of MRL/+, MRL/lpr (that manifest lupus-like phenotype) and MRL/lpr-Fn14 knockout (Fn14ko) adult female mice to determine the transcriptomic impact of TWEAK/Fn14 on cortical gene expression in lupus. We found that the TWEAK/Fn14 pathway strongly affects the expression level, variability and coordination of the genomic fabrics responsible for neurotransmission and chemokine signaling. Dysregulation of the Phosphoinositide 3-kinase (PI3K)-AKT pathway in the MRL/lpr lupus strain compared with the MRL/+ control and Fn14ko mice was particularly prominent and, therefore, promising as a potential therapeutic target, although the complexity of the transcriptomic fabric highlights important considerations in in vivo experimental models. Full article
(This article belongs to the Special Issue Genomic Fabric Remodeling in Neurological Disorders)
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26 pages, 15414 KiB  
Article
Cellular Environment Remodels the Genomic Fabrics of Functional Pathways in Astrocytes
by Dumitru A Iacobas, Sanda Iacobas, Randy F Stout and David C Spray
Genes 2020, 11(5), 520; https://doi.org/10.3390/genes11050520 - 7 May 2020
Cited by 12 | Viewed by 3708
Abstract
We profiled the transcriptomes of primary mouse cortical astrocytes cultured alone or co-cultured with immortalized precursor oligodendrocytes (Oli-neu cells). Filters between the cell types prevented formation of hetero-cellular gap junction channels but allowed for free exchange of the two culture media. We [...] Read more.
We profiled the transcriptomes of primary mouse cortical astrocytes cultured alone or co-cultured with immortalized precursor oligodendrocytes (Oli-neu cells). Filters between the cell types prevented formation of hetero-cellular gap junction channels but allowed for free exchange of the two culture media. We previously reported that major functional pathways in the Oli-neu cells are remodeled by the proximity of non-touching astrocytes and that astrocytes and oligodendrocytes form a panglial transcriptomic syncytium in the brain. Here, we present evidence that the astrocyte transcriptome likewise changes significantly in the proximity of non-touching Oli-neu cells. Our results indicate that the cellular environment strongly modulates the transcriptome of each cell type and that integration in a heterocellular tissue changes not only the expression profile but also the expression control and networking of the genes in each cell phenotype. The significant decrease of the overall transcription control suggests that in the co-culture astrocytes are closer to their normal conditions from the brain. The Oli-neu secretome regulates astrocyte genes known to modulate neuronal synaptic transmission and remodels calcium, chemokine, NOD-like receptor, PI3K-Akt, and thyroid hormone signaling, as well as actin-cytoskeleton, autophagy, cell cycle, and circadian rhythm pathways. Moreover, the co-culture significantly changes the gene hierarchy in the astrocytes. Full article
(This article belongs to the Special Issue Genomic Fabric Remodeling in Neurological Disorders)
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