Abstract 18889: Circulating microRNA Implicated in the TGF-β Signalling Pathway are Altered in Marfan Syndrome

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Elizabeth N Robertson ◽  
Yaxin Lu ◽  
Alex Sahagian ◽  
Donna Lai ◽  
Murat Kekic ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiovascular Disease ◽  
Marfan Syndrome ◽  
Regulation Of Gene Expression ◽  
Left Ventricular ◽  
Microrna Expression ◽  
Aortic Aneurysms ◽  
Circulating Microrna ◽  
Transcriptional Level ◽  
Aortic Dilatation

Thoracic aortic aneurysms in Marfan Syndrome (MFS) caused by mutations in FBN1 are associated with altered TGF-β signaling. Regulation of gene expression can occur at the level of microRNA, which can modify signaling pathways. We hypothesized that there would be altered microRNA expression in MFS that may alter the expression of signaling proteins. Total RNA was isolated from whole blood collected in PAXgene® tubes (PreAnalytiX), from 13 MFS patients with aortic dilatation (6F, 7M; Ao Diameter 44.4±6.0mm; Age 39±12yrs) and 10 normal controls (5F, 5M; Ao Diameter 32.3±5mm; Age 34±10yrs). The RNA was reverse transcribed with Human Pool A & B primers and qPCR was performed on the subsequent cDNA using TaqMan® OpenArray® Human miRNA Panels (2454 targets) (ThermoFisher). microRNA expression was considered to be significantly altered if there was >2 fold change (p<0.05) compared to controls. microRNA that were identified as significantly altered were then validated with qPCR using targeted primers on an additional 33 MFS patients (15F, 21M; Ao Diameter 44.2±5.0mm; Age 37±13yrs). In MFS patients, the OpenArray® identified 30 microRNA were significantly altered (22 up regulated, 8 down regulated). Of these, 12 were confirmed to be altered using targeted qPCR (Graph 1). Three of these have previously been identified as modifiers of the TGF-β signaling pathway (miR 17, miR 93, miR 93*). Three were from the let-7 family (let-7e, let-7f, let-7g), which are involved in terminal cell differentiation and have been implicated in several cardiovascular disease processes. Another three have been shown to be dysregulated in various cardiovascular disease states including atherosclerotic thoracic aortic aneurysm and left ventricular hypertrophy (miR 208, miR 486, miR 378). This study provides novel evidence for adaptive responses at the post-transcriptional level of gene expression that may modulate aneurysm development in Marfan syndrome.

Glutathione system participation in thoracic aneurysms from patients with Marfan syndrome

VASA ◽  
2017 ◽  
Vol 46 (3) ◽  
pp. 177-186 ◽  
Author(s):  
Alejandra María Zúñiga-Muñoz ◽  
Israel Pérez-Torres ◽  
Verónica Guarner-Lans ◽  
Elías Núñez-Garrido ◽  
Rodrigo Velázquez Espejel ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Marfan Syndrome ◽  
Aortic Aneurysms ◽  
Aortic Dilatation ◽  
Glutathione S Transferase ◽  
Reduced And Oxidized Glutathione ◽  
Total Antioxidant ◽  
Elevated Activity ◽  
Acute Dissection ◽  
Thoracic Aneurysms

Abstract. Background: Aortic dilatation in Marfan syndrome (MFS) is progressive. It is associated with oxidative stress and endothelial dysfunction that contribute to the early acute dissection of the vessel and can result in rupture of the aorta and sudden death. We evaluated the participation of the glutathione (GSH) system, which could be involved in the mechanisms that promote the formation and progression of the aortic aneurysms in MFS patients. Patients and methods: Aortic aneurysm tissue was obtained during chest surgery from eight control subjects and 14 MFS patients. Spectrophotometrical determination of activity of glutathione peroxidase (GPx), glutathione-S-transferase (GST), glutathione reductase (GR), lipid peroxidation (LPO) index, carbonylation, total antioxidant capacity (TAC), and concentration of reduced and oxidized glutathione (GSH and GSSG respectively), was performed in the homogenate from aortic aneurysm tissue. Results: LPO index, carbonylation, TGF-β1, and GR activity were increased in MFS patients (p < 0.04), while TAC, GSH/GSSG ratio, GPx, and GST activity were significantly decreased (p < 0.04). Conclusions: The depletion of GSH, in spite of the elevated activity of GR, not only diminished the activity of GSH-depend GST and GPx, but increased LPO, carbonylation and decreased TAC. These changes could promote the structural and functional alterations in the thoracic aorta of MFS patients.

Regulation of gene expression during spermatogenesis at transcriptional level

2011 ◽  
Vol 33 (12) ◽  
pp. 1300-1307
Author(s):  
Xiu-Jun ZHANG ◽  
Mei-Ling LIU ◽  
Meng-Chun JIA
Keyword(s):  
Gene Expression ◽  
Regulation Of Gene Expression ◽  
Transcriptional Level

scholarly journals Regulation of proton-translocating V-ATPases.

1997 ◽  
Vol 200 (2) ◽  
pp. 225-235 ◽  
Author(s):  
H Merzendorfer ◽  
R Gräf ◽  
M Huss ◽  
W R Harvey ◽  
H Wieczorek
Keyword(s):  
Gene Expression ◽  
Enzyme Activity ◽  
Plasma Membranes ◽  
Regulation Of Gene Expression ◽  
Transcriptional Level ◽  
Structural Domains ◽  
Sh Groups ◽  
Signalling Molecules ◽  
Membrane Spanning ◽  
Regulation Of Enzyme Activity

Vacuolar-type ATPases (V-ATPases) are proton-translocating enzymes that occur in the endomembranes of all eukaryotes and in the plasma membranes of many eukaryotes. They are multisubunit, heteromeric proteins composed of two structural domains, a peripheral, catalytic V1 domain and a membrane-spanning V0 domain. Both the multitude of locations and the heteromultimeric structure make it likely that the expression and the activity of V-ATPases are regulated in various ways. Regulation of gene expression encompasses control of transcription as well as control at the post-transcriptional level. Regulation of enzyme activity encompasses many diverse mechanisms such as disassembly/reassembly of V1 and V0 domains, oxidation of SH groups, control by activator and inhibitor proteins or by small signalling molecules, and sorting of the holoenzyme or its subunits to target membranes.

scholarly journals Epigenetic Research in Stem Cell Bioengineering—Anti-Cancer Therapy, Regenerative and Reconstructive Medicine in Human Clinical Trials

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 1016 ◽  
Author(s):  
Claudia Dompe ◽  
Krzysztof Janowicz ◽  
Greg Hutchings ◽  
Lisa Moncrieff ◽  
Maurycy Jankowski ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Trials ◽  
Stem Cell ◽  
Cancer Therapy ◽  
Regulation Of Gene Expression ◽  
Epigenetic Modifications ◽  
Transcriptional Level ◽  
Cancer Therapies ◽  
Stem Cell Engineering ◽  
Anti Cancer

The epigenome denotes all the information related to gene expression that is not contained in the DNA sequence but rather results from chemical changes to histones and DNA. Epigenetic modifications act in a cooperative way towards the regulation of gene expression, working at the transcriptional or post-transcriptional level, and play a key role in the determination of phenotypic variations in cells containing the same genotype. Epigenetic modifications are important considerations in relation to anti-cancer therapy and regenerative/reconstructive medicine. Moreover, a range of clinical trials have been performed, exploiting the potential of epigenetics in stem cell engineering towards application in disease treatments and diagnostics. Epigenetic studies will most likely be the basis of future cancer therapies, as epigenetic modifications play major roles in tumour formation, malignancy and metastasis. In fact, a large number of currently designed or tested clinical approaches, based on compounds regulating epigenetic pathways in various types of tumours, employ these mechanisms in stem cell bioengineering.

scholarly journals Circular RNAs in Cardiovascular Disease: An Overview

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Ximin Fan ◽  
Xinyu Weng ◽  
Yifan Zhao ◽  
Wei Chen ◽  
Tianyi Gan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiovascular Disease ◽  
Cardiovascular Diseases ◽  
Noncoding Rna ◽  
Essential Role ◽  
Closed Loop ◽  
Regulation Of Gene Expression ◽  
Circular Rna ◽  
Circular Rnas ◽  
Mirna Sponges

Circular RNA (circRNA), a novel type of endogenous noncoding RNA (ncRNA), has become a research hotspot in recent years. CircRNAs are abundant and stably exist in creatures, and they are found with covalently closed loop structures in which they are quite different from linear RNAs. Nowadays, an increasing number of scientists have demonstrated that circRNAs may have played an essential role in the regulation of gene expression, especially acting as miRNA sponges, and have described the potential mechanisms of several circRNAs in diseases, hinting at their clinical therapeutic values. In this review, the authors summarized the current understandings of the biogenesis and properties of circRNAs and their functions and role as biomarkers in cardiovascular diseases.

scholarly journals miR-155 Inhibits Expression of the MEF2A Protein to Repress Skeletal Muscle Differentiation

2011 ◽  
Vol 286 (41) ◽  
pp. 35339-35346 ◽  
Author(s):  
Hee Young Seok ◽  
Mariko Tatsuguchi ◽  
Thomas E. Callis ◽  
Aibin He ◽  
William T. Pu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Small Rnas ◽  
Myogenic Differentiation ◽  
Regulation Of Gene Expression ◽  
Myoblast Differentiation ◽  
Transcriptional Level ◽  
Muscle Gene Expression ◽  
Important Regulator ◽  
Non Coding Rnas ◽  
Muscle Gene

microRNAs (miRNAs) are 21–23-nucleotide non-coding RNAs. It has become more and more evident that this class of small RNAs plays critical roles in the regulation of gene expression at the post-transcriptional level. MEF2A is a member of the MEF2 (myogenic enhancer factor 2) family of transcription factors. Prior report showed that the 3′-untranslated region (3′-UTR) of the Mef2A gene mediated its repression; however, the molecular mechanism underlying this intriguing observation was unknown. Here, we report that MEF2A is repressed by miRNAs. We identify miR-155 as one of the primary miRNAs that significantly represses the expression of MEF2A. We show that knockdown of the Mef2A gene by siRNA impairs myoblast differentiation. Similarly, overexpression of miR-155 leads to the repression of endogenous MEF2A expression and the inhibition of myoblast differentiation. Most importantly, reintroduction of MEF2A in miR-155 overexpressed myoblasts was able to partially rescue the miR-155-induced myoblast differentiation defect. Our data therefore establish miR-155 as an important regulator of MEF2A expression and uncover its function in muscle gene expression and myogenic differentiation.

scholarly journals Marfan Syndrome, A Review

2018 ◽  
Vol 4 (2) ◽  
pp. 33
Author(s):  
Gerard Pals
Keyword(s):  
Marfan Syndrome ◽  
Index Finger ◽  
The Body ◽  
Aortic Aneurysms ◽  
Tall Stature ◽  
Aortic Dilatation ◽  
Thoracic Aortic Aneurysms ◽  
Ocular Symptoms ◽  
Arm Span ◽  
Lens Luxation

Marfan syndrome is named after the French pediatrician Antoine Bernard-Jean Marfan who described in 1896 a girl with arachnodactyly and long limbs1. The patient also had congenital contractures of the elbows and would not fulfill the current criteria for Marfan syndrome. She probably was suffering from a condition that we now call contractural arachnodactyly, caused by mutations in the FBN2 gene.The clinical features of Marfan syndrome affect many systems of the body. The most obvious are the skeletal features, long limbs, tall stature, long thin fingers (arachnodactyly or spider fingers). The skeletal features can be scored objectively as: arm span more than 1.05 x body length; wrist sign (thumb and index finger can encircle the wrist of the other hand with at least one digit overlap) and thumb sign (when making a fist around the thumb, one digit of the thumb sticks out). The main neurological symptom is dural ectasias. The most severe symptoms are cardiovascular: mitralis valve prolapse, aortic dilatation and thoracic aortic aneurysms and dissections, which may lead to sudden death5. However, I noticed in discussions with patients that they often consider the ocular symptoms, severe myopia and lens luxation, the worst for themselves, because the latter may lead to blindness.

scholarly journals Mechanisms Regulating Abnormal Circular RNA Biogenesis in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4185
Author(s):  
Ying Huang ◽  
Qubo Zhu
Keyword(s):  
Gene Expression ◽  
Regulation Of Gene Expression ◽  
Circular Rna ◽  
Regulatory Elements ◽  
Circular Rnas ◽  
Transcriptional Level ◽  
Closed Loops ◽  
Rna Biogenesis ◽  
Cis And Trans ◽  
Functional Mechanisms

Circular RNAs (circRNAs), which are a class of endogenous RNA with covalently closed loops, play important roles in epigenetic regulation of gene expression at both the transcriptional and post-transcriptional level. Accumulating evidence demonstrated that numerous circRNAs were abnormally expressed in tumors and their dysregulation was involved in the tumorigenesis and metastasis of cancer. Although the functional mechanisms of many circRNAs have been revealed, how circRNAs are dysregulated in cancer remains elusive. CircRNAs are generated by a “back-splicing” process, which is regulated by different cis-regulatory elements and trans-acting proteins. Therefore, how these cis and trans elements change during tumorigenesis and how they regulate the biogenesis of circRNAs in cancer are two questions that interest us. In this review, we summarized the pathways for the biogenesis of circRNAs; and then illustrated how circRNAs dysregulated in cancer by discussing the changes of cis-regulatory elements and trans-acting proteins that related to circRNA splicing and maturation in cancer.

scholarly journals Low Affinity Binding Sites in an Activating CRM Mediate Negative Autoregulation of the Drosophila Hox Gene Ultrabithorax

2019 ◽  
Author(s):  
Rebecca K Delker ◽  
Vikram Ranade ◽  
Ryan Loker ◽  
Roumen Voutev ◽  
Richard S Mann
Keyword(s):  
Gene Expression ◽  
Binding Sites ◽  
Transcriptional Control ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Transcriptional Level ◽  
Regulation Of Transcription ◽  
Control Of Gene Expression ◽  
Hox Gene ◽  
Endogenous Locus

AbstractSpecification of cell identity and the proper functioning of a mature cell depend on precise regulation of gene expression. Both binary ON/OFF regulation of transcription, as well as more fine-tuned control of transcription levels in the ON state, are required to define cell types. The Drosophila melanogaster Hox gene, Ultrabithorax (Ubx), exhibits both of these modes of control during development. While ON/OFF regulation is needed to specify the fate of the developing wing (Ubx OFF) and haltere (Ubx ON), the levels of Ubx within the haltere differ between compartments along the proximal-distal axis. Here, we identify and molecularly dissect the novel contribution of a previously identified Ubx cis-regulatory module (CRM), anterobithorax (abx), to a negative auto-regulatory loop that maintains decreased Ubx expression in the proximal compartment of the haltere as compared to the distal compartment. We find that Ubx, in complex with the known Hox cofactors, Homothorax (Hth) and Extradenticle (Exd), acts through low-affinity Ubx-Exd binding sites to reduce the levels of Ubx transcription in the proximal compartment. Importantly, we also reveal that Ubx-Exd-binding site mutations sufficient to result in de-repression of abx activity in the proximal haltere in a transgenic context are not sufficient to de-repress Ubx expression when mutated at the endogenous locus, suggesting the presence of multiple mechanisms through which Ubx-mediated repression occurs. Our results underscore the complementary nature of CRM analysis through transgenic reporter assays and genome modification of the endogenous locus; but, they also highlight the increasing need to understand gene regulation within the native context to capture the potential input of multiple genomic elements on gene control.Author SummaryOne of the most fundamental questions in biology is how information encoded in the DNA is translated into the diversity of cell-types that exist within a multicellular organism, each with the same genome. Regulation at the transcriptional level, mediated through the activity of transcription factors bound to cis-regulatory modules (CRMs), plays a key role in this process. While we typically distinguish cell-type by the specific subset of genes that are transcriptionally ON or OFF, it is also important to consider the more fine-tuned transcriptional control of gene expression level. We focus on the regulatory logic of the Hox developmental regulator, Ultrabithorax (Ubx), in fruit flies, which exhibits both forms of transcriptional control. While ON/OFF control of Ubx is required to define differential appendage fate in the T2 and T3 thoracic segments, respectively, more fine-tuned control of transcription levels is observed in distinct compartments within the T3 appendage, itself, in which all cells exhibit a Ubx ON state. Through genetic analysis of regulatory inputs, and dissection of a Ubx CRM in a transgenic context and at the endogenous locus, we reveal a compartment-specific negative autoregulatory loop that dampens Ubx transcription to maintain distinct transcriptional levels within a single developing tissue.

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