scholarly journals Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma

2021 ◽  
Vol 28 (12) ◽  
pp. 757-772
Author(s):  
Luise Eckardt ◽  
Maria Prange-Barczynska ◽  
Emma J Hodson ◽  
James W Fielding ◽  
Xiaotong Cheng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Pattern ◽  
Adult Life ◽  
General Role ◽  
Spatially Resolved ◽  
High Heritability ◽  
Cellular Oxygen ◽  
Developmental Role ◽  
Hif Prolyl Hydroxylase

Despite a general role for the HIF hydroxylase system in cellular oxygen sensing and tumour hypoxia, cancer-associated mutations of genes in this pathway, including PHD2, PHD1, EPAS1 (encoding HIF-2α) are highly tissue-restricted, being observed in pseudohypoxic pheochromocytoma and paraganglioma (PPGL) but rarely, if ever, in other tumours. In an effort to understand that paradox and gain insights into the pathogenesis of pseudohypoxic PPGL, we constructed mice in which the principal HIF prolyl hydroxylase, Phd2, is inactivated in the adrenal medulla using TH-restricted Cre recombinase. Investigation of these animals revealed a gene expression pattern closely mimicking that of pseudohypoxic PPGL. Spatially resolved analyses demonstrated a binary distribution of two contrasting patterns of gene expression among adrenal medullary cells. Phd2 inactivation resulted in a marked shift in this distribution towards a Pnmt−/Hif-2α+/Rgs5+ population. This was associated with morphological abnormalities of adrenal development, including ectopic TH+ cells within the adrenal cortex and external to the adrenal gland. These changes were ablated by combined inactivation of Phd2 with Hif-2α, but not Hif-1α. However, they could not be reproduced by inactivation of Phd2 in adult life, suggesting that they arise from dysregulation of this pathway during adrenal development. Together with the clinical observation that pseudohypoxic PPGL manifests remarkably high heritability, our findings suggest that this type of tumour likely arises from dysregulation of a tissue-restricted action of the PHD2/HIF-2α pathway affecting adrenal development in early life and provides a model for the study of the relevant processes.

Distinct gene expression patterns in chronic lymphocytic leukemia defined by usage of specific VH genes

Blood ◽  
2006 ◽  
Vol 107 (5) ◽  
pp. 2090-2093 ◽  
Author(s):  
Dirk Kienle ◽  
Axel Benner ◽  
Alexander Kröber ◽  
Dirk Winkler ◽  
Daniel Mertens ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Lymphocytic Leukemia ◽  
Expression Patterns ◽  
Gene Expression Pattern ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Expression Of Genes ◽  
Vh Genes ◽  
Signaling Activation

The mutation status and usage of specific VH genes such as V3-21 and V1-69 are potentially independent pathogenic and prognostic factors in chronic lymphocytic leukemia (CLL). To investigate the role of antigenic stimulation, we analyzed the expression of genes involved in B-cell receptor (BCR) signaling/activation, cell cycle, and apoptosis control in CLL using these specific VH genes compared to VH mutated (VH-MUT) and VH unmutated (VH-UM) CLL not using these VH genes. V3-21 cases showed characteristic expression differences compared to VH-MUT (up: ZAP70 [or ZAP-70]; down: CCND2, P27) and VH-UM (down: PI3K, CCND2, P27, CDK4, BAX) involving several BCR-related genes. Similarly, there was a marked difference between VH unmutated cases using the V1-69 gene and VH-UM (up: FOS; down: BLNK, SYK, CDK4, TP53). Therefore, usage of specific VH genes appears to have a strong influence on the gene expression pattern pointing to antigen recognition and ongoing BCR stimulation as a pathogenic factor in these CLL subgroups.

scholarly journals miR-185 and SEPT5 Genes May Contribute to Parkinson’s Disease Pathophysiology

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Arman Rahimmi ◽  
Ilaria Peluso ◽  
Aref Rajabi ◽  
Kambiz Hassanzadeh
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Chromosomal Location ◽  
Gene Expression Pattern ◽  
Control Group ◽  
Significant Difference

There are still unknown mechanisms involved in the development of Parkinson’s disease (PD), which elucidating them can assist in developing efficient therapies. Recently, studies showed that genes located on the human chromosomal location 22q11.2 might be involved in the development of PD. Therefore, the present study was designed to evaluate the role of two genes located on the chromosomal location (miR-185 and SEPT5), which were the most probable candidates based on our bibliography. In vivo and in vitro models of PD were developed using male Wistar rats and SHSY-5Y cell line, respectively. The expression levels of miR-185, SEPT5, LRRK2, and PARK2 genes were measured at a mRNA level in dopaminergic areas of rats’ brains and SHSY-5Y cells using the SYBR Green Real-Time PCR Method. Additionally, the effect of inhibition on the genes or their products on cell viability and gene expression pattern in SHSY-5Y cells was investigated. The level of miR-185 gene expression was significantly decreased in the substantia nigra (SN) and striatum (ST) of the rotenone-treated group (control group) compared to the healthy normal group (P<0.05). In addition, there was a significant difference in the expression of SEPT5 gene (P<0.05) in the substantia nigra between two studied groups. The results of an in vitro study showed no significant change in the expression of the genes; however, the inhibition on miR-185 gene expression led to the increase in LRRK2 gene expression in SHSY-5Y cells. The inhibition on LRRK2 protein also decreased the cellular toxicity effect of rotenone on SHSY-5Y cells. The results suggested the protective role of miR-185 gene in preventing the development of PD.

scholarly journals Transcriptional Enhancers in Drosophila

Genetics ◽  
2020 ◽  
Vol 216 (1) ◽  
pp. 1-26 ◽  
Author(s):  
Stephen Small ◽  
David N. Arnosti
Keyword(s):  
Gene Expression ◽  
Critical Role ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Comprehensive Analysis ◽  
Special Focus ◽  
Transcriptional Enhancers ◽  
Quantitative Understanding ◽  
Developmental Role

Key discoveries in Drosophila have shaped our understanding of cellular “enhancers.” With a special focus on the fly, this chapter surveys properties of these adaptable cis-regulatory elements, whose actions are critical for the complex spatial/temporal transcriptional regulation of gene expression in metazoa. The powerful combination of genetics, molecular biology, and genomics available in Drosophila has provided an arena in which the developmental role of enhancers can be explored. Enhancers are characterized by diverse low- or high-throughput assays, which are challenging to interpret, as not all of these methods of identifying enhancers produce concordant results. As a model metazoan, the fly offers important advantages to comprehensive analysis of the central functions that enhancers play in gene expression, and their critical role in mediating the production of phenotypes from genotype and environmental inputs. A major challenge moving forward will be obtaining a quantitative understanding of how these cis-regulatory elements operate in development and disease.

scholarly journals Role of Histone-Like Proteins H-NS and StpA in Expression of Virulence Determinants of Uropathogenic Escherichia coli

2006 ◽  
Vol 188 (15) ◽  
pp. 5428-5438 ◽  
Author(s):  
Claudia M. Müller ◽  
Ulrich Dobrindt ◽  
Gábor Nagy ◽  
Levente Emödy ◽  
Bernt Eric Uhlin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Escherichia Coli ◽  
Gene Expression Pattern ◽  
Direct Interaction ◽  
Virulence Determinants ◽  
Dna Arrays ◽  
Infectious Dose ◽  
E Coli ◽  
Huge Impact

ABSTRACT The histone-like protein H-NS is a global regulator in Escherichia coli that has been intensively studied in nonpathogenic strains. However, no comprehensive study on the role of H-NS and its paralogue, StpA, in gene expression in pathogenic E. coli has been carried out so far. Here, we monitored the global effects of H-NS and StpA in a uropathogenic E. coli isolate by using DNA arrays. Expression profiling revealed that more than 500 genes were affected by an hns mutation, whereas no effect of StpA alone was observed. An hns stpA double mutant showed a distinct gene expression pattern that differed in large part from that of the hns single mutant. This suggests a direct interaction between the two paralogues and the existence of distinct regulons of H-NS and an H-NS/StpA heteromeric complex. hns mutation resulted in increased expression of alpha-hemolysin, fimbriae, and iron uptake systems as well as genes involved in stress adaptation. Furthermore, several other putative virulence genes were found to be part of the H-NS regulon. Although the lack of H-NS, either alone or in combination with StpA, has a huge impact on gene expression in pathogenic E. coli strains, its effect on virulence is ambiguous. At a high infection dose, hns mutants trigger more sudden lethality due to their increased acute toxicity in murine urinary tract infection and sepsis models. At a lower infectious dose, however, mutants lacking H-NS are attenuated through their impaired growth rate, which can only partially be compensated for by the higher expression of numerous virulence factors.

scholarly journals Stress signaling and STAT1 activation characterize the keratinocytic gene expression pattern in Hidradenitis suppurativa

2021 ◽  
Author(s):  
VG Frings ◽  
L Jopp ◽  
M Srivastava ◽  
D Presser ◽  
M Goebeler ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Rna Sequencing ◽  
Expression Pattern ◽  
Hidradenitis Suppurativa ◽  
Gene Expression Pattern ◽  
Epidermal Keratinocytes ◽  
Stress Signaling ◽  
Promising Therapeutic Approach

ABSTRACTBackgroundThe underlying pathogenetic factors generating the innate immune signal necessary for T cell activation, initiation and chronification of Hidradenitis suppurativa (HS, also known as Acne inversa) are still poorly understood. Emerging evidence suggests that defective keratinocyte function critically contributes to HS disease development and progression.ObjectivesTo elucidate the role of keratinocytes in HS lesion formation, we compared the transcriptomes of isolated lesional and perilesional HS epidermis by RNA sequencing.MethodsLesional and perilesional HS skin samples of at least 3 different donors were obtained. Isolated epidermal keratinocytes were further processed for cell culture, protein extraction, immunostaining procedures or RNA isolation and RNA sequencing. For large scale promotor site analysis, DEGs were analyzed for overrepresented transcription factor binding sites. Functional annotation clustering for analyzing enriched functional-related gene groups was performed employing the DAVID Bioinformatics Resources.ResultsWe show that HS is characterized by a strong epidermal stress state as evident by a significant overrepresentation of an AP-1-driven stress signature in the overall gene expression pattern of lesional keratinocytes and a substantial activation of the stress-activated cJun N-terminal kinase (JNK) pathway in lesional HS epidermis. Additionally, our data reveal a strong induction of STAT1 activation in lesional HS epidermis that likely results from IFNγ production and governs the expression of key inflammatory genes that coordinate activation of innate immunity and the adaptive T cell response in HS.ConclusionsTaken together, these data implicate a new role of combined stress signaling and JAK/STAT1 pathway activation in disease progression of HS suggesting interference with JAK/STAT1 signaling as a potentially promising therapeutic approach for HS.

scholarly journals Gene expression profiling identifies FLT3 mutation-like cases in wild-type FLT3 acute myeloid leukemia

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0247093
Author(s):  
Adrián Mosquera Orgueira ◽  
Andrés Peleteiro Raíndo ◽  
Miguel Cid López ◽  
Beatriz Antelo Rodríguez ◽  
José Ángel Díaz Arias ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Pattern ◽  
Gene Expression Pattern ◽  
Wild Type ◽  
Wilcoxon Rank Sum Test ◽  
Recurrent Mutations ◽  
Flt3 Inhibitors ◽  
Predictive Role ◽  
Acute Myeloid

Background FLT3 mutation is present in 25–30% of all acute myeloid leukemias (AML), and it is associated with adverse outcome. FLT3 inhibitors have shown improved survival results in AML both as upfront treatment and in relapsed/refractory disease. Curiously, a variable proportion of wild-type FLT3 patients also responded to these drugs. Methods We analyzed 6 different transcriptomic datasets of AML cases. Differential expression between mutated and wild-type FLT3 AMLs was performed with the Wilcoxon-rank sum test. Hierarchical clustering was used to identify FLT3-mutation like AMLs. Finally, enrichment in recurrent mutations was performed with the Fisher’s test. Results A FLT3 mutation-like gene expression pattern was identified among wild-type FLT3 AMLs. This pattern was highly enriched in NPM1 and DNMT3A mutants, and particularly in combined NPM1/DNMT3A mutants. Conclusions We identified a FLT3 mutation-like gene expression pattern in AML which was highly enriched in NPM1 and DNMT3A mutations. Future analysis about the predictive role of this biomarker among wild-type FLT3 patients treated with FLT3 inhibitors is envisaged.

scholarly journals Are sex-biased genes more dispensable?

2009 ◽  
Vol 5 (3) ◽  
pp. 409-412 ◽  
Author(s):  
Judith E. Mank ◽  
Hans Ellegren
Keyword(s):  
Gene Expression ◽  
Sexual Selection ◽  
Molecular Evolution ◽  
Gene Expression Pattern ◽  
Selective Constraint ◽  
Sexually Dimorphic ◽  
Males And Females ◽  
Natural And Sexual Selection ◽  
Rates Of Molecular Evolution

Many genes show different expression levels in males and females, and these form the basis of sexually dimorphic phenotypes. Sex-biased genes experience accelerated rates of protein evolution, which has been attributed to sexual selection. However, it is possible that the increased rates of molecular evolution, and more importantly the sex-biased gene expression pattern itself, are due to decreased selective constraint. This notion may explain many of the patterns associated with sex-biased gene expression, and changes how we should view the role of natural and sexual selection in relation to these genes.

scholarly journals Sphingolipid Metabolic Pathway: An Overview of Major Roles Played in Human Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Raghavendra Pralhada Rao ◽  
Nanditha Vaidyanathan ◽  
Mathiyazhagan Rengasamy ◽  
Anup Mammen Oommen ◽  
Neeti Somaiya ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Expression Pattern ◽  
Metabolic Pathway ◽  
Membrane Lipids ◽  
Gene Expression Pattern ◽  
Bioactive Molecules ◽  
Cellular Processes ◽  
Key Players

Sphingolipids, a family of membrane lipids, are bioactive molecules that participate in diverse functions controlling fundamental cellular processes such as cell division, differentiation, and cell death. Given that most of these cellular processes form the basis for several pathologies, it is not surprising that sphingolipids are key players in several pathological processes. This review discusses the role of the sphingolipid metabolic pathway in diabetes, Alzheimer’s disease, and hepatocellular carcinoma, with a special emphasis on the changes in gene expression pattern in these disease conditions. For convenience, the sphingolipid metabolic pathway is divided into hypothetical compartments (modules) with each compartment representing a physiological process and changes in gene expression pattern are mapped to each of these modules. It appears that alterations in the gene expression pattern in these disease conditions are biased to manipulate the system in order to result in a particular disease.

Sign in / Sign up

Export Citation Format

Share Document