Myocardium transcriptomes of left and right atria and ventricles from four adult male C57Bl/6j mice were profiled with Agilent microarrays to identify the differences responsible for the distinct ...functional roles of the four heart chambers. Female mice were not investigated owing to their transcriptome dependence on the estrous cycle phase. Out of the quantified 16,886 unigenes, 15.76% on the left side and 16.5% on the right side exhibited differential expression between the atrium and the ventricle, while 5.8% of genes were differently expressed between the two atria and only 1.2% between the two ventricles. The study revealed also chamber differences in gene expression control and coordination. We analyzed ion channels and transporters, and genes within the cardiac muscle contraction, oxidative phosphorylation, glycolysis/gluconeogenesis, calcium and adrenergic signaling pathways. Interestingly, while expression of Ank2 oscillates in phase with all 27 quantified binding partners in the left ventricle, the percentage of in-phase oscillating partners of Ank2 is 15% and 37% in the left and right atria and 74% in the right ventricle. The analysis indicated high interventricular synchrony of the ion channels expressions and the substantially lower synchrony between the two atria and between the atrium and the ventricle from the same side.
Low-salt diet (LSD) is a constant recommendation to hypertensive patients, but the genomic mechanisms through which it improves cardiac pathophysiology are still not fully understood. Our publicly ...accessible transcriptomic dataset of the left ventricle myocardium of adult male mice subjected to prolonged LSD or normal diet was analyzed from the perspective of the Genomic Fabric Paradigm. We found that LSD shifted the metabolic priorities by increasing the transcription control for fatty acids biosynthesis while decreasing it for steroid hormone biosynthesis. Moreover, LSD remodeled pathways responsible for cardiac muscle contraction (CMC), chronic Chagas (CHA), diabetic (DIA), dilated (DIL), and hypertrophic (HCM) cardiomyopathies, and their interplays with the glycolysis/glucogenesis (GLY), oxidative phosphorylation (OXP), and adrenergic signaling in cardiomyocytes (ASC). For instance, the statistically (
< 0.05) significant coupling between GLY and ASC was reduced by LSD from 13.82% to 2.91% (i.e., -4.75×), and that of ASC with HCM from 10.50% to 2.83% (-3.71×). The substantial up-regulation of the CMC, ASC, and OXP genes, and the significant weakening of the synchronization of the expression of the HCM, CHA, DIA, and DIL genes within their respective fabrics justify the benefits of the LSD recommendation.
Publicly available (own) transcriptomic data have been analyzed to quantify the alteration in functional pathways in thyroid cancer, establish the gene hierarchy, identify potential gene targets and ...predict the effects of their manipulation. The expression data have been generated by profiling one case of papillary thyroid carcinoma (PTC) and genetically manipulated BCPAP (papillary) and 8505C (anaplastic) human thyroid cancer cell lines. The study used the genomic fabric paradigm that considers the transcriptome as a multi-dimensional mathematical object based on the three independent characteristics that can be derived for each gene from the expression data. We found remarkable remodeling of the thyroid hormone synthesis, cell cycle, oxidative phosphorylation and apoptosis pathways. Serine peptidase inhibitor, Kunitz type, 2 (
) was identified as the Gene Master Regulator of the investigated PTC. The substantial increase in the expression synergism of
with apoptosis genes in the cancer nodule with respect to the surrounding normal tissue (NOR) suggests that
experimental overexpression may force the PTC cells into apoptosis with a negligible effect on the NOR cells. The predictive value of the expression coordination for the expression regulation was validated with data from 8505C and BCPAP cell lines before and after lentiviral transfection with
Decades of research identified genomic similarities among prostate cancer patients and proposed general solutions for diagnostic and treatments. However, each human is a dynamic unique with never ...repeatable transcriptomic topology and no gene therapy is good for everybody. Therefore, we propose the Genomic Fabric Paradigm (GFP) as a personalized alternative to the biomarkers approach. Here, GFP is applied to three (one primary—“A”, and two secondary—“B” & “C”) cancer nodules and the surrounding normal tissue (“N”) from a surgically removed prostate tumor. GFP proved for the first time that, in addition to the expression levels, cancer alters also the cellular control of the gene expression fluctuations and remodels their networking. Substantial differences among the profiled regions were found in the pathways of P53-signaling, apoptosis, prostate cancer, block of differentiation, evading apoptosis, immortality, insensitivity to anti-growth signals, proliferation, resistance to chemotherapy, and sustained angiogenesis. ENTPD2, AP5M1 BAIAP2L1, and TOR1A were identified as the master regulators of the “A”, “B”, “C”, and “N” regions, and potential consequences of ENTPD2 manipulation were analyzed. The study shows that GFP can fully characterize the transcriptomic complexity of a heterogeneous prostate tumor and identify the most influential genes in each cancer nodule.
The dynamic and never exactly repeatable tumor transcriptomic profile of people affected by the same form of cancer requires a personalized and time-sensitive approach of the gene therapy. The Gene ...Master Regulators (GMRs) were defined as genes whose highly controlled expression by the homeostatic mechanisms commands the cell phenotype by modulating major functional pathways through expression correlation with their genes. The Gene Commanding Height (GCH), a measure that combines the expression control and expression correlation with all other genes, is used to establish the gene hierarchy in each cell phenotype. We developed the experimental protocol, the mathematical algorithm and the computer software to identify the GMRs from transcriptomic data in surgically removed tumors, biopsies or blood from cancer patients. The GMR approach is illustrated with applications to our microarray data on human kidney, thyroid and prostate cancer samples, and on thyroid, prostate and blood cancer cell lines. We proved experimentally that each patient has his/her own GMRs, that cancer nuclei and surrounding normal tissue are governed by different GMRs, and that manipulating the expression has larger consequences for genes with higher GCH. Therefore, we launch the hypothesis that silencing the GMR may selectively kill the cancer cells from a tissue.
Gene regulatory networks underlie the long-term changes in cell specification, growth of synaptic connections, and adaptation that occur throughout neonatal and postnatal life. Here we show that the ...transcriptional response in neurons is exquisitely sensitive to the temporal nature of action potential firing patterns. Neurons were electrically stimulated with the same number of action potentials, but with different inter-burst intervals. We found that these subtle alterations in the timing of action potential firing differentially regulates hundreds of genes, across many functional categories, through the activation or repression of distinct transcriptional networks. Our results demonstrate that the transcriptional response in neurons to environmental stimuli, coded in the pattern of action potential firing, can be very sensitive to the temporal nature of action potential delivery rather than the intensity of stimulation or the total number of action potentials delivered. These data identify temporal kinetics of action potential firing as critical components regulating intracellular signalling pathways and gene expression in neurons to extracellular cues during early development and throughout life.
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 (
,
,
) 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.
Pulmonary hypertension (PH) is a serious disorder with high morbidity and mortality rate. We analyzed the right-ventricular systolic pressure (RVSP), right-ventricular hypertrophy (RVH), lung ...histology, and transcriptomes of six-week-old male rats with PH induced by (1) hypoxia (HO), (2) administration of monocrotaline (CM), or (3) administration of monocrotaline and exposure to hypoxia (HM). The results in PH rats were compared to those in control rats (CO). After four weeks exposure, increased RVSP and RVH, pulmonary arterial wall thickening, and alteration of the lung transcriptome were observed in all PH groups. The HM group exhibited the largest alterations, as well as neointimal lesions and obliteration of the lumen in small arteries. We found that PH increased the expression of caveolin1, matrix metallopeptidase 2, and numerous inflammatory and cell proliferation genes. The cell cycle, vascular smooth muscle contraction, and oxidative phosphorylation pathways, as well as their interplay, were largely perturbed. Our results also suggest that the upregulated
(Ras homolog family member A) mediates its action through expression coordination with several ATPases. The upregulation of antioxidant genes and the extensive mitochondrial damage observed, especially in the HM group, indicate metabolic shift toward aerobic glycolysis.
Transcriptional responses to the appropriate temporal pattern of action potential firing are essential for long-term adaption of neuronal properties to the functional activity of neural circuits and ...environmental experience. However, standard transcriptome analysis methods can be too limited in identifying critical aspects that coordinate temporal coding of action potential firing with transcriptome response. A Pearson correlation analysis was applied to determine how pairs of genes in the mouse dorsal root ganglion (DRG) neurons are coordinately expressed in response to stimulation producing the same number of action potentials by two different temporal patterns. Analysis of 4728 distinct gene-pairs related to calcium signaling, 435,711 pairs of transcription factors, 820 pairs of voltage-gated ion channels, and 86,862 pairs of calcium signaling genes with transcription factors indicated that genes become coordinately activated by distinct action potential firing patterns and this depends on the duration of stimulation. Moreover, a measure of expression variance revealed that the control of transcripts abundances is sensitive to the pattern of stimulation. Thus, action potentials impact intracellular signaling and the transcriptome in dynamic manner that not only alter gene expression levels significantly (as previously reported) but also affects the control of their expression fluctuations and profoundly remodel the transcriptional networks.
Women with epilepsy commonly have premature onset of menopause. The decrease in estrogen levels is associated with increased occurrence of neurodegenerative processes and cognitive decline. ...Previously, we found that estradiol (E2) replacement in ovariectomized (OVX) female rats significantly reduced the seizure-related damage in the sensitive hilar region of hippocampal dentate gyrus (DG). However, the complex mechanisms by which E2 empowers the genomic fabrics of neurotransmission to resist damaging effects of status epilepticus (SE) are still unclear. We determined the protective effects of the estradiol replacement against kainic acid-induced SE-associated transcriptomic alterations in the DG of OVX rats. Without E2 replacement, SE altered expression of 44% of the DG genes. SE affected all major functional pathways, including apoptosis (61%), Alzheimer's disease (47%), cell cycle (59%), long-term potentiation (62%), and depression (55%), as well as synaptic vesicle cycle (62%), glutamatergic (53%), GABAergic (49%), cholinergic (52%), dopaminergic (55%), and serotonergic (49%) neurotransmission. However, in rats with E2 replacement the percentage of significantly affected genes after SE was reduced to the average 11% (from 8% for apoptosis to 32% for GABAergic synapse). Interestingly, while SE down-regulated most of the synaptic receptor genes in oil-injected females it had little effect on these receptors after E2-replacement. Our novel Pathway Protection analysis indicated that the E2-replacement prevented SE-related damage from 50% for GABA to 75% for dopaminergic transmission. The 15% synergistic expression between genes involved in estrogen signaling (ESG) and neurotransmission explains why low E2 levels result in down-regulation of neurotransmission. Interestingly, in animals with E2-replacement, SE switched 131 synergistically expressed ESG-neurotransmission gene pairs into antagonistically expressed gene pairs. Thus, the ESG pathway acts like a buffer against SE-induced alteration of neurotransmission that may contribute to the E2-mediated maintenance of brain function after the SE injury in postmenopausal women. We also show that the long-term potentiation is lost in OVX rats following SE but not in those with E2 replacement. The electrophysiological findings in OVX female rats with SE are corroborated by the high percentage of long-term potentiation regulated genes (62%) in oil-injected while only 13% of genes were regulated following SE in E2-replaced rats.
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