Role Of Changes In Gene Expression Research Articles

Transcriptomic Analysis of Peripheral Artery Disease Patient Derived Myotubes Reveals Broad Gene Expression Changes and Alternative Splicing

Peripheral Artery Disease (PAD) is a disease characterized by atherosclerosis of the arteries suppling blood to the lower extremities. One of the clinical manifestations of PAD is myopathy of the affected muscles. In order to elucidate the role of gene expression changes in myotubes and their effect on PAD myopathy, we isolated myotubes from PAD and control patients to perform transcriptomic analysis. We hypothesized that myogenic and muscle contractility related gene expression levels change during PAD. Our analysis revealed 690 significant differentially expressed genes. Gene ontology analysis showed significant increase in genes relating to myogenesis and muscle contraction. Hypoxia and mitochondria related genes were also dysregulated in PAD myotubes. Kegg pathway analysis showed genes enriched in muscle contraction pathways as well as adrenergic signaling. Alternative splicing analysis showed 209 genes with differential transcript isoform expression. Gene ontology showed that these genes relate to cell adhesion, apoptosis and autophagy. qPCR and Protein expression analysis confirms some of these transcriptional changes. This study shows the need for further exploration into how transcriptional changes affect the development of myopathies and the progression of PAD. It also shows the ability for isolation patient myotubes as a model for the study of myopathies in PAD.

PPARα polymorphisms association with total cholesterol and LDL-C levels in a Mexican population.

Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear transcription factor with a role in gene expression changes associated to lipid metabolism. PPARα polymorphic variants have been previously correlated to serum lipid profile but in Mexico, there is no previous report about that association. For this reason, the aim of this study was to investigate the relationship between PPARα polymorphic variants and lipids level in serum in a Mexican population. Two-hundred and forty women from the Northeast region of Mexico were included in the study. Anthropometric characteristics and serum lipid profile (such as triglycerides, total cholesterol, LDL cholesterol and HDL cholesterol) were evaluated. Genomic DNA extraction and purification were made from blood samples. Real-time PCR and TaqMan probes were used for genotyping of rs1800206 and rs4253778 single nucleotide polymorphisms (SNPs). Linear regression analysis (adjusted by age and body mass index (BMI)) showed a significant statistical association of rs4253778 with total cholesterol (p=0.034) and LDL cholesterol (p=0.037). Any significant association was found between rs1800206 and lipid levels. These results suggested that rs4253778 (C allele) is associated with high levels of total cholesterol and LDL in a Mexican women population.

Checkpoint activation drives global gene expression changes in Drosophila nuclear lamina mutants.

The nuclear lamina (NL) lines the inner nuclear membrane. This extensive protein network organizes chromatin and contributes to the regulation of transcription, DNA replication, and repair. Lap2-emerin-MAN1 domain (LEM-D) proteins are key members of the NL, representing proteins that connect the NL to the genome through shared interactions with the chromatin-binding protein Barrier-to-Autointegration Factor (BAF). Functions of the LEM-D protein emerin and BAF are essential during Drosophila melanogaster oogenesis. Indeed, loss of either emerin or BAF blocks germ cell development and causes loss of germline stem cells, defects linked to the deformation of NL structure, and non-canonical activation of Checkpoint kinase 2 (Chk2). Here, we investigate the contributions of emerin and BAF to gene expression in the ovary. Profiling RNAs from emerin and baf mutant ovaries revealed that nearly all baf misregulated genes were shared with emerin mutants, defining a set of NL-regulated genes. Strikingly, loss of Chk2 restored the expression of most NL-regulated genes, identifying a large class of Chk2-dependent genes (CDGs). Nonetheless, some genes remained misexpressed upon Chk2 loss, identifying a smaller class of emerin-dependent genes (EDGs). Properties of EDGs suggest a shared role for emerin and BAF in the repression of developmental genes. Properties of CDGs demonstrate that Chk2 activation drives global misexpression of genes in the emerin and baf mutant backgrounds. Notably, CDGs were found upregulated in lamin-B mutant backgrounds. These observations predict that Chk2 activation might have a general role in gene expression changes found in NL-associated diseases, such as laminopathies.

Altered Gene Expression in Acne Vulgaris Patients Treated by Oral Isotretinoin: A Preliminary Study.

Background/ObjectiveThe role of gene expression changes in acne patients treated by oral isotretinoin (ISO) and in influencing the ISO therapeutic effects is still unclear. In this study, we investigated the gene profiles of patients with severe acne who responded variously to ISO therapy.MethodsThe peripheral blood of 113 acne vulgaris patients (Pillsbury IV grade) was collected before treatment. After 8 weeks of oral ISO, nine acne patients were selected and divided into the following groups. A: effectively treated by ISO, group B: ineffectively treated by ISO, group C: ISO-induced acne flare-up, and 3 healthy subjects were included as control group D. The peripheral blood of patients pre- and post-treatment was subjected to high-throughput RNA sequencing technology and bioinformatics analysis of the separate groups (n = 3). The candidate genes were validated by qRT-PCR.ResultsComparing pre- and post-oral ISO treatment, gene expression was changed as 39 genes in ISO-effective group, 345 genes in ISO-ineffective group, and 57 genes in ISO-induced acne flare-up group. Comparing the ISO-induced acne flare-up group with healthy control subjects revealed 34 upregulated genes and 23 downregulated genes, while comparing the ISO-induced acne flare-up group with ISO-ineffective patients identified 1835 changed genes. Expression of GATA2 (2.73 fold, P=0.024512), C4BPA (35.87 folds, P=0.038073), and CCR5 (2.48 folds, P=0.004681) increased in the ISO-induced acne flare-up patients. Meanwhile, the expression of DEFA3 (0.18 fold, P=0.041934), ELANE (0.14 fold, P=0.030767), MMP9 (0.41 fold, P=0.013383), and RPS4Y1 (0.00018 fold, P=0.000986) decreased when compared with ISO-ineffective patients.ConclusionOral ISO treatment could temporarily alter gene expression in acne patients. ISO therapeutic mechanisms were involved, not only in regulating the inflammatory reaction but also in the process of DNA repair. GATA2, C4BPA, CCR5, DEFA3, ELANE, MMP9, and RPS4Y1 might be susceptible to genes that could participate in the ISO-induced aggravation of acne.

The Role of Gene Expression Changes in ceRNA Network Underlying Ossification of Ligamentum Flavum Development.

We aimed at exploring the role of gene expression changes regulated by non-coding RNAs in ossification of ligamentum flavum (OLF). Three microarray datasets, including long non-coding RNA (lncRNA)/mRNA expression profile (GSE106253), circular RNA (circRNA) expression profile (GSE106255), and microRNA (miRNA) expression profile (GSE106256), were downloaded from the public Gene Expression Omnibus repository. The differentially expressed (DE) mRNAs, lncRNAs, miRNAs, and circRNAs in OLF tissues were analyzed, compared with normal tissues. Two competing endogenous RNA (ceRNA) networks with lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA interactions were constructed, separately. Random walk with the restart model was applied to calculate the correlations of mRNAs with the published OLF-related genes. The top 50 mRNAs were subjected to function enrichment analysis and active small-molecule prediction. Total 2323 DE mRNAs, 1168 lncRNAs, 336 circRNAs, and 29 miRNAs were identified based on the microarray datasets. The LncRNA-related ceRNA network was constructed with 614 lncRNA-miRNA, 494 miRNA-mRNA, and 2099 lncRNA-mRNA interaction pairs; the circRNA-related ceRNA network was constructed with 153 circRNA-miRNA, 190 miRNA-mRNA, and 210 circRNA-mRNA interaction pairs. There were 17 OLF-related genes retrieved from previous literature, such as NPPS, COL6A1, and COL11A2, among which COL6A1 was the overlapped gene with mRNAs in the ceRNA network. Subsequently, top 50 mRNAs that closely correlated with COL6A1 in the ceRNA network were captured and these genes were closely related with the collagen catabolic process, regulation of cell growth, and neuronal action potential. DRD1 and COL6A1 were predicted to be the targets by small active molecule drugs. The collagen catabolic process may be implicated in OLF development. COL6A1 and DRD1 may be the candidate targets for OLF. However, further validations were needed.

Bcl-2 and Bax proteins are increased in neocortical but not in thalamic apoptosis following devascularizing lesion of the cerebral cortex in the rat: an immunohistochemical study

The hypothesis that devascularization of somatosensory and motor cortex causes apoptosis in infarcted regions and in the linked thalamic nuclei was evaluated. To unravel whether Bcl-related proteins, known to regulate apoptosis, participate in neuronal and glial responses to devascularization, we analyzed immunohistochemically the distribution and intensity of staining of Bcl-2 and Bax proteins at different time points after lesion. Both early (up to 6 h) and late (1–7 days) responses were studied. Devascularization led to rapid (within hours) apoptosis in the cortex and to a delayed (within 3–7 days) apoptosis in thalamic nuclei. In control groups, Bcl-2 and Bax immunoreactivity (IR) was detected in neurons and oligodendrocytes but not in astrocytes or microglia. Following devascularization, Bcl-2 IR and Bax IR increased in neurons before the onset of the apoptosis. In the ischemic focus, the increase reached maximal values 3 h after the lesion. The increase was of slower onset in the penumbra zone (24 h and after), a region in which both proteins were induced in astrocytes also. The change of Bax IR intensity exceeded four times that of Bcl-2 at all time points investigated, indicating a diminution of Bcl-2/Bax ratio that may direct neurons to apoptotic pathway. In numerous neurons, an increase of IR in the cytoplasm was accompanied by induction of nuclear staining. No changes of Bcl-2 and Bax IR were found in thalamic nuclei. Our results point to different mechanisms underlying apoptosis of cortical and thalamic neurons. Nuclear appearance of Bcl-2 and Bax suggests they possess regulatory role of gene expression changes triggered by cortical infarct.

An interactive database of cocaine-responsive gene expression.

The postgenomic era of large-scale gene expression studies is inundating drug abuse researchers and many other scientists with findings related to gene expression. This information is distributed across many different journals, and requires laborious literature searches. Here, we present an interactive database that combines existing information related to cocaine-mediated changes in gene expression in an easy-to-use format. The database is limited to statistically significant changes in mRNA or protein expression after cocaine administration. The Flash-based program is integrated into a Web page, and organizes changes in gene expression based on neuroanatomical region, general function, and gene name. Accompanying each gene is a description of the gene, links to the original publications, and a link to the appropriate OMIM (Online Mendelian Inheritance in Man) entry. The nature of this review allows for timely modifications and rapid inclusion of new publications, and should help researchers build second-generation hypotheses on the role of gene expression changes in the physiology and behavior of cocaine abuse. Furthermore, this method of organizing large volumes of scientific information can easily be adapted to assist researchers in fields outside of drug abuse.

Hyperalgesia and amino acids: Receptor selectivity based on stimulus intensity and a role for peptides

Summary The reader may have noted that we have tried to restrict our discussion to mechanisms of cutaneous hyperalgesia. We have taken the liberty to include some discussion of hyperalgesia produced by inflammation of deeper tissues and articular spaces since these conditions appear to share many mechanisms in common with cutaneous hyperalgesia. We have carefully avoided a discussion of the mechanisms underlying hyperalgesia produced by injury to viscera or nervous tissue because space constraints do not permit us to address the special issues that pertain to these conditions. Dr. Meller's thesis outlines an interesting new perspective on the chemical mechanisms of hyperalgesia. Although the widely accepted preexisting intensity-based hypothesis may not yet account for all aspects of hyperalgesia, it does account for a large body of psychophysical data as well as experimental data that has been gathered from study of the dorsal horn alone. It is not at all clear that this previously established hypothesis has been refuted, or that Dr. Meller's alternate hypothesis better accounts for this same body of information. Finally, we have avoided commentary on the potential role of second messenger systems and gene expression modifications that may be involved in the generation-expression of hyperalgesia given the complexity of the neurotransmitter mechanisms. Dr. Meller should be applauded for the service he does indicating the multiplicity in second messenger systems that may potentially be involved. However, his scheme will likely require extensive modification. Allowances need to be made for the messenger systems of the neuropeptides and for the issue of multiplicity in the mechanisms for expression-maintenance of hyperalgesia. For example, a recent publication by Minami et al. 61 illustrates that interactions between cyclooxygenase products and excitatory amino acids can involve either of the excitatory amino acid receptor subtypes. Thus, this final issue, as well as the role of gene expression changes, will no doubt be an area of research increasingly addressed in many future studies.