scholarly journals Meiotic interactors of a mitotic geneTAO3revealed by functional analysis of its rare variant

2015 ◽  
Author(s):  
Saumya Gupta ◽  
Aparna Radhakrishnan ◽  
Rachana Nitin ◽  
Pandu Raharja-Liu ◽  
Gen Lin ◽  
...  
Keyword(s):  
Target Gene ◽  
Tricarboxylic Acid Cycle ◽  
Complex Trait ◽  
Rare Allele ◽  
Time Resolved ◽  
Sporulation Efficiency ◽  
Ram Network ◽  
Functional Consequences ◽  
Rare Genetic Variants

ABSTRACTStudying the molecular consequences of rare genetic variants has the potential of identifying novel and hereto uncharacterized pathways causally contributing to phenotypic variation. Here we characterize the functional consequences of a rare coding variant ofTAO3, previously reported to significantly contribute to sporulation efficiency variation inSaccharomyces cerevisiae. During mitosisTAO3interacts withCBK1, a conserved NDR kinase and a component of RAM network. The RAM network genes are involved in regulation cell separation and polarization. We demonstrate that the role of the rare alleleTAO3(4477C)in meiosis is distinct from its role in mitosis by being independent ofACE2, which is a RAM network target gene. By quantitatively measuring cell morphological dynamics and conditionally expressingTAO3(4477C)allele during sporulation, we show thatTAO3has an early role in meiosis. This early role ofTAO3coincides with entry of cells into meiotic division. Time-resolved transcriptome analyses during early sporulation phase identified regulators of carbon and lipid metabolic pathways as candidate mediators. We experimentally show that during sporulation theTAO3allele genetically interacts withERT1andPIP2, the regulators of tricarboxylic acid cycle and gluconeogenic enzymes, respectively. We thus uncover meiotic functions ofTAO3, a mitotic gene and proposeERT1andPIP2as novel regulators of sporulation efficiency. Our results demonstrate that study of causal effects of genetic variation on the underlying molecular network has the potential to provide more extensive comprehension of the pathways driving a complex trait. This can help identify prospective personalized targets for intervention in complex diseases.

scholarly journals CHOP-Dependent Stress-Inducible Expression of a Novel Form of Carbonic Anhydrase VI

1999 ◽  
Vol 19 (1) ◽  
pp. 495-504 ◽  
Author(s):  
John Sok ◽  
Xiao-Zhong Wang ◽  
Nikoleta Batchvarova ◽  
Masahiko Kuroda ◽  
Heather Harding ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Target Gene ◽  
Target Genes ◽  
Direct Evidence ◽  
Nuclear Protein ◽  
Intracellular Form ◽  
Carbonic Anhydrase Vi ◽  
Responsive Element

ABSTRACT CHOP (also called GADD153) is a stress-inducible nuclear protein that dimerizes with members of the C/EBP family of transcription factors and was initially identified as an inhibitor of C/EBP binding to classic C/EBP target genes. Subsequent experiments suggested a role for CHOP-C/EBP heterodimers in positively regulating gene expression; however, direct evidence that this is the case has so far not been uncovered. Here we describe the identification of a positively regulated direct CHOP-C/EBP target gene, that encoding murine carbonic anhydrase VI (CA-VI). The stress-inducible form of the gene is expressed from an internal promoter and encodes a novel intracellular form of what is normally a secreted protein. Stress-induced expression of CA-VI is both CHOP and C/EBPβ dependent in that it does not occur in cells deficient in either gene. A CHOP-responsive element was mapped to the inducibleCA-VI promoter, and in vitro footprinting revealed binding of CHOP-C/EBP heterodimers to that site. Rescue of CA-VIexpression in c/ebpβ−/− cells by exogenous C/EBPβ and a shorter, normally inhibitory isoform of the protein known as LIP suggests that the role of the C/EBP partner is limited to targeting the CHOP-containing heterodimer to the response element and points to a preeminent role for CHOP in CA-VI induction during stress.

scholarly journals The Role of Cell Metabolism in Innate Immune Memory

2020 ◽  
pp. 1-9
Author(s):  
Anaisa Valido Ferreira ◽  
Jorge Domiguéz-Andrés ◽  
Mihai Gheorghe Netea
Keyword(s):  
Metabolic Pathways ◽  
Tricarboxylic Acid Cycle ◽  
Cell Metabolism ◽  
Innate Immune ◽  
Immune Memory ◽  
Functional Changes ◽  
Trained Immunity ◽  
Health And Disease

Immunological memory is classically attributed to adaptive immune responses, but recent studies have shown that challenged innate immune cells can display long-term functional changes that increase nonspecific responsiveness to subsequent infections. This phenomenon, coined <i>trained immunity</i> or <i>innate immune memory</i>, is based on the epigenetic reprogramming and the rewiring of intracellular metabolic pathways. Here, we review the different metabolic pathways that are modulated in trained immunity. Glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, amino acid, and lipid metabolism are interplaying pathways that are crucial for the establishment of innate immune memory. Unraveling this metabolic wiring allows for a better understanding of innate immune contribution to health and disease. These insights may open avenues for the development of future therapies that aim to harness or dampen the power of the innate immune response.

scholarly journals Isoform-Specific Roles of Mutant p63 in Human Diseases

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 536
Author(s):  
Christian Osterburg ◽  
Susanne Osterburg ◽  
Huiqing Zhou ◽  
Caterina Missero ◽  
Volker Dötsch
Keyword(s):  
Cleft Lip ◽  
Ectodermal Dysplasia ◽  
Skin Development ◽  
Disease Mechanisms ◽  
Skin Fragility ◽  
Cleft Lip Palate ◽  
Life Threatening ◽  
Functional Consequences ◽  
Development And Differentiation

The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the DNA binding domain cause Ectrodactyly, Ectodermal Dysplasia, characterized by limb deformation, cleft lip/palate, and ectodermal dysplasia while mutations in in the C-terminal domain of the α-isoform cause Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility, severe, long-lasting skin erosions, and cleft lip/palate. The molecular disease mechanisms of these syndromes have recently become elucidated and have enhanced our understanding of the role of p63 in epidermal development. Here we review the molecular cause and functional consequences of these p63-mutations for skin development and discuss the consequences of p63 mutations for female fertility.

scholarly journals Advances in the role of miRNAs in the occurrence and development of osteosarcoma

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 1003-1011
Author(s):  
Guanyu Zhang ◽  
Yiran Li ◽  
Jiasheng Xu ◽  
Zhenfang Xiong
Keyword(s):  
Target Gene ◽  
Early Stage ◽  
Research Direction ◽  
Research Progress ◽  
Skeletal System ◽  
Translation Process ◽  
Non Coding Rnas ◽  
New Research ◽  
Post Transcriptional Regulation

AbstractOsteosarcoma (OS) is the most common primary malignant tumor of the skeletal system in the clinic. It mainly occurs in adolescent patients and the pathogenesis of the disease is very complicated. The distant metastasis may occur in the early stage, and the prognosis is poor. MicroRNAs (miRNAs) are non-coding RNAs of about 18–25 nt in length that are involved in post-transcriptional regulation of genes. miRNAs can regulate target gene expression by promoting the degradation of target mRNAs or inhibiting the translation process, thereby the proliferation of OS cells can be inhibited and the apoptosis can be promoted; in this way, miRNAs can affect the metabolism of OS cells and can also participate in the occurrence, invasion, metastasis, and recurrence of OS. Some miRNAs have already been found to be closely related to the prognosis of patients with OS. Unlike other reviews, this review summarizes the miRNA molecules closely related to the development, diagnosis, prognosis, and treatment of OS in recent years. The expression and influence of miRNA molecule on OS were discussed in detail, and the related research progress was summarized to provide a new research direction for early diagnosis and treatment of OS.

scholarly journals Glucocorticoid receptor wields chromatin interactions to tune transcription for cytoskeleton stabilization in podocytes

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Hong Wang ◽  
Aiping Duan ◽  
Jing Zhang ◽  
Qi Wang ◽  
Yuexian Xing ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Glucocorticoid Receptor ◽  
Protective Effect ◽  
Histone Modification ◽  
Regulatory Networks ◽  
Target Gene ◽  
Regulatory Elements ◽  
Chromatin Interactions ◽  
Super Enhancer

AbstractElucidating transcription mediated by the glucocorticoid receptor (GR) is crucial for understanding the role of glucocorticoids (GCs) in the treatment of diseases. Podocyte is a useful model for studying GR regulation because GCs are the primary medication for podocytopathy. In this study, we integrated data from transcriptome, transcription factor binding, histone modification, and genome topology. Our data reveals that the GR binds and activates selective regulatory elements in podocyte. The 3D interactome captured by HiChIP facilitates the identification of remote targets of GR. We found that GR in podocyte is enriched at transcriptional interaction hubs and super-enhancers. We further demonstrate that the target gene of the top GR-associated super-enhancer is indispensable to the effective functioning of GC in podocyte. Our findings provided insights into the mechanisms underlying the protective effect of GCs on podocyte, and demonstrate the importance of considering transcriptional interactions in order to fine-map regulatory networks of GR.

scholarly journals TCA Cycle and Fatty Acids Oxidation Reflect Early Cardiorenal Damage in Normoalbuminuric Subjects with Controlled Hypertension

Antioxidants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1100
Author(s):  
Aranzazu Santiago-Hernandez ◽  
Marta Martin-Lorenzo ◽  
Ariadna Martin-Blazquez ◽  
Gema Ruiz-Hurtado ◽  
Maria G Barderas ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Tricarboxylic Acid Cycle ◽  
Renin Angiotensin System ◽  
Roc Curves ◽  
Tca Cycle ◽  
Urinary Metabolites ◽  
Organ Damage ◽  
Fatty Acid Binding ◽  
Angiotensin System

Moderately increased albuminuria, defined by an albumin to creatinine ratio (ACR) > 30 mg/g, is an indicator of subclinical organ damage associated with a higher risk of cardiovascular and renal disease. Normoalbuminuric subjects are considered at no cardiorenal risk in clinical practice, and molecular changes underlying early development are unclear. To decipher subjacent mechanisms, we stratified the normoalbuminuria condition. A total of 37 hypertensive patients under chronic renin–angiotensin system (RAS) suppression with ACR values in the normoalbuminuria range were included and classified as control (C) (ACR < 10 mg/g) and high-normal (HN) (ACR = 10–30 mg/g). Target metabolomic analysis was carried out by liquid chromatography and mass spectrometry to investigate the role of the cardiorenal risk urinary metabolites previously identified. Besides this, urinary free fatty acids (FFAs), fatty acid binding protein 1 (FABP1) and nephrin were analyzed by colorimetric and ELISA assays. A Mann–Whitney test was applied, ROC curves were calculated and Spearman correlation analysis was carried out. Nine metabolites showed significantly altered abundance in HN versus C, and urinary FFAs and FABP1 increased in HN group, pointing to dysregulation in the tricarboxylic acid cycle (TCA) cycle and fatty acids β-oxidation. We showed here how cardiorenal metabolites associate with albuminuria, already in the normoalbuminuric range, evidencing early renal damage at a tubular level and suggesting increased β-oxidation to potentially counteract fatty acids overload in the HN range.

scholarly journals Prediction of Functional Consequences of Missense Mutations in ANO4 Gene

2021 ◽  
Vol 22 (5) ◽  
pp. 2732
Author(s):  
Nadine Reichhart ◽  
Vladimir M. Milenkovic ◽  
Christian H. Wetzel ◽  
Olaf Strauß
Keyword(s):  
Transmembrane Protein ◽  
Functional Characterization ◽  
Missense Mutations ◽  
Mutant Proteins ◽  
Functional Consequences ◽  
New Perspective ◽  
The Stability ◽  
Dynamics Simulations ◽  
And Function

The anoctamin (TMEM16) family of transmembrane protein consists of ten members in vertebrates, which act as Ca2+-dependent ion channels and/or Ca2+-dependent scramblases. ANO4 which is primarily expressed in the CNS and certain endocrine glands, has been associated with various neuronal disorders. Therefore, we focused our study on prioritizing missense mutations that are assumed to alter the structure and stability of ANO4 protein. We employed a wide array of evolution and structure based in silico prediction methods to identify potentially deleterious missense mutations in the ANO4 gene. Identified pathogenic mutations were then mapped to the modeled human ANO4 structure and the effects of missense mutations were studied on the atomic level using molecular dynamics simulations. Our data show that the G80A and A500T mutations significantly alter the stability of the mutant proteins, thus providing new perspective on the role of missense mutations in ANO4 gene. Results obtained in this study may help to identify disease associated mutations which affect ANO4 protein structure and function and might facilitate future functional characterization of ANO4.

scholarly journals Identification of Autosomal Regions Involved in Drosophila Raf Function

Genetics ◽  
2000 ◽  
Vol 156 (2) ◽  
pp. 763-774 ◽  
Author(s):  
Willis Li ◽  
Elizabeth Noll ◽  
Norbert Perrimon
Keyword(s):  
Limb Development ◽  
Target Gene ◽  
Biological Function ◽  
Genetic Interaction ◽  
Ectopic Expression ◽  
Tor Signaling ◽  
Downstream Effector ◽  
Early Embryos ◽  
Genomic Regions

Abstract Raf is an essential downstream effector of activated p21Ras (Ras) in transducing proliferation or differentiation signals. Following binding to Ras, Raf is translocated to the plasma membrane, where it is activated by a yet unidentified “Raf activator.” In an attempt to identify the Raf activator or additional molecules involved in the Raf signaling pathway, we conducted a genetic screen to identify genomic regions that are required for the biological function of Drosophila Raf (Draf). We tested a collection of chromosomal deficiencies representing ∼70% of the autosomal euchromatic genomic regions for their abilities to enhance the lethality associated with a hypomorphic viable allele of Draf, DrafSu2. Of the 148 autosomal deficiencies tested, 23 behaved as dominant enhancers of Draf  Su2, causing lethality in Draf  Su2 hemizygous males. Four of these deficiencies identified genes known to be involved in the Drosophila Ras/Raf (Ras1/Draf) pathway: Ras1, rolled (rl, encoding a MAPK), 14-3-3ϵ, and bowel (bowl). Two additional deficiencies removed the Drosophila Tec and Src homologs, Tec29A and Src64B. We demonstrate that Src64B interacts genetically with Draf and that an activated form of Src64B, when overexpressed in early embryos, causes ectopic expression of the Torso (Tor) receptor tyrosine kinase-target gene tailless. In addition, we show that a mutation in Tec29A partially suppresses a gain-of-function mutation in tor. These results suggest that Tec29A and Src64B are involved in Tor signaling, raising the possibility that they function to activate Draf. Finally, we discovered a genetic interaction between Draf  Su2 and Df(3L)vin5 that revealed a novel role of Draf in limb development. We find that loss of Draf activity causes limb defects, including pattern duplications, consistent with a role for Draf in regulation of engrailed (en) expression in imaginal discs.

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