Marfan Syndrome Variability: Investigation of the Roles of Sarcolipin and Calcium as Potential Transregulator of FBN1 Expression

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that displays a great clinical variability. Previous work in our laboratory showed that fibrillin-1 (FBN1) messenger RNA (mRNA) expression is a surrogate endpoint for MFS severity. Therefore, an expression quantitative trait loci (eQTL) analysis was performed to identify trans-acting regulators of FBN1 expression, and a significant signal reached genome-wide significant threshold on chromosome 11. This signal delineated a region comprising one expressed gene, SLN (encoding sarcolipin), and a single pseudogene, SNX7-ps1 (CTD-2651C21.3). We first investigated the region and then looked for association between the genes in the region and FBN1 expression. For the first time, we showed that the SLN gene is weakly expressed in skin fibroblasts. There is no direct correlation between SLN and FBN1 gene expression. We showed that calcium influx modulates FBN1 gene expression. Finally, SLN gene expression is highly correlated to that of the neighboring SNX7-ps1. We were able to confirm the impact of calcium influx on FBN1 gene expression but we could not conclude regarding the role of sarcolipin and/or the eQTL locus in this regulation.

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Reference Expression Profile of Three FBN1 Transcript Isoforms and Their Association with Clinical Variability in Marfan Syndrome

Genes ◽

10.3390/genes10020128 ◽

2019 ◽

Vol 10 (2) ◽

pp. 128

Author(s):

Louise Benarroch ◽

Mélodie Aubart ◽

Marie-Sylvie Gross ◽

Pauline Arnaud ◽

Nadine Hanna ◽

...

Keyword(s):

Marfan Syndrome ◽

Age Of Onset ◽

Expression Profiles ◽

Phenotypic Variability ◽

Surrogate Endpoint ◽

Connective Tissue Disorder ◽

Clinical Variability ◽

Fbn1 Gene ◽

Adventitial Fibroblasts ◽

Alternatively Spliced

Marfan syndrome (MFS) is a rare connective tissue disorder mainly due to mutations in the FBN1 gene. Great phenotypic variability is notable for age of onset, the presence and absence, and the number and the severity of the symptoms. Our team showed that FBN1 gene expression level was a good surrogate endpoint for severity of some MFS clinical features. Eight alternative transcripts are referenced for the FBN1 gene. We hypothesized that MFS clinical variability could be related to specific FBN1 isoforms. Isoform expression profiles were investigated in skin and adventitial fibroblasts from controls and MFS patients. The results of the study showed that, in skin and adventitial fibroblasts, only three isoforms were found: FBN1_001, FBN1_004, and FBN1_009. The main isoform was FBN1_001 and it was significantly reduced in skin and adventitial fibroblasts of MFS patients. The expressions of FBN1_004 and FBN1_009 isoforms were similar between controls and MFS patients. However, the expression of the three isoforms was correlated only in patients. Furthermore, their expression levels were associated with the presence of ectopia lentis in MFS patients. Therefore, our results highlight that the two minor alternatively spliced FBN1 isoforms play a possible role in the pathogenesis of the disease.

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MicroRNA-377 Alleviates Myocardial Injury Induced by Hypoxia/Reoxygenation via Downregulating LILRB2 Expression

Dose-Response ◽

10.1177/1559325820936124 ◽

2020 ◽

Vol 18 (2) ◽

pp. 155932582093612 ◽

Cited By ~ 2

Author(s):

Mengwei Xie ◽

Chunlan Hu ◽

Delin Li ◽

Shifeng Li

Keyword(s):

Gene Expression ◽

Myocardial Infarction ◽

Messenger Rna ◽

Myocardial Injury ◽

Cell Activity ◽

Gene Expression Omnibus ◽

Luciferase Reporter ◽

Data Set ◽

The Impact ◽

Hypoxia Reoxygenation

Background: miR-377 is closely related to myocardial regeneration. miR-377-adjusted mesenchymal stem cells abducted ischemic cardiac angiogenesis. Nevertheless, there were rarely reports about the impact of miR-377 on myocardial ischemia injury. The purpose of this work is that whether miR-377 can protect against myocardial injury caused by hypoxia/reoxygenation (H/R). Methods: Gene expression omnibus database ( http://www.ncbi.nlm.nih.gov/geo/ ; no. GSE53211) was utilized to study the differential expression of miR-377 in patients with an acute ST-segment elevation myocardial infarction and healthy controls. The luciferase activity was determined utilizing the dual-luciferase reporter system. Quantitative real-time polymerase chain reaction and Western blotting were used to measure the messenger RNA and protein level. Results: Low expression of miR-377 and high expression of leukocyte immunoglobulin-like receptor B2 (LILRB2) were identified in patients with myocardial infarction from analyzing the Gene Expression Omnibus data set. Besides, miR-377 expression was downregulated in cardiomyocyte exposed to H/R. Additionally, overexpression of miR-377 could visibly improve cardiomyocyte injury by regulating cell activity and apoptosis. Conclusions: In short, our findings suggested that miR-377/LILRB2 might regard as a hopeful therapeutic target for myocardial ischemic.

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Translation inhibition and resource balance in the TX-TL cell-free gene expression system

Synthetic Biology ◽

10.1093/synbio/ysx005 ◽

2017 ◽

Vol 2 (1) ◽

Cited By ~ 14

Author(s):

Vijayalakshmi H Nagaraj ◽

James M Greene ◽

Anirvan M Sengupta ◽

Eduardo D Sontag

Keyword(s):

Gene Expression ◽

Messenger Rna ◽

Resource Dependence ◽

Alternative Hypothesis ◽

Expression System ◽

Resource Limitation ◽

Independent Effect ◽

Translation Rate ◽

Suppression Of Gene Expression ◽

The Impact

Abstract Quantifying the effect of vital resources on transcription (TX) and translation (TL) helps to understand the degree to which the concentration of each resource must be regulated for achieving homeostasis. Utilizing the synthetic TX-TL system, we study the impact of nucleotide triphosphates (NTPs) and magnesium (Mg2+) on gene expression. Recent observations of the counter-intuitive phenomenon of suppression of gene expression at high NTP concentrations have led to the speculation that such suppression is due to the consumption of resources by TX, hence leaving fewer resources for TL. In this work, we investigate an alternative hypothesis: direct suppression of the TL rate via stoichiometric mismatch in necessary reagents. We observe NTP-dependent suppression even in the early phase of gene expression, contradicting the resource-limitation argument. To further decouple the contributions of TX and TL, we performed gene expression experiments with purified messenger RNA (mRNA). Simultaneously monitoring mRNA and protein abundances allowed us to extract a time-dependent translation rate. Measuring TL rates for different Mg2+ and NTP concentrations, we observe a complex resource dependence. We demonstrate that TL is the rate-limiting process that is directly inhibited by high NTP concentrations. Additional Mg2+ can partially reverse this inhibition. In several experiments, we observe two maxima of the TL rate viewed as a function of both Mg2+ and NTP concentration, which can be explained in terms of an NTP-independent effect on the ribosome complex and an NTP-Mg2+ titration effect. The non-trivial compensatory effects of abundance of different vital resources signal the presence of complex regulatory mechanisms to achieve optimal gene expression.

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A Novel Heterozygous Intronic Mutation in the FBN1 Gene Contributes to FBN1 RNA Missplicing Events in the Marfan Syndrome

BioMed Research International ◽

10.1155/2018/3536495 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Mario Torrado ◽

Emilia Maneiro ◽

Juan Pablo Trujillo-Quintero ◽

Arturo Evangelista ◽

Alexander T. Mikhailov ◽

...

Keyword(s):

Connective Tissue ◽

Marfan Syndrome ◽

Premature Termination Codon ◽

Connective Tissue Disorder ◽

Aortic Dilatation ◽

Functional Protein ◽

Fbn1 Gene ◽

Intronic Mutation ◽

Aortic Pathology ◽

Fibrillin 1

Marfan syndrome (MFS) is an autosomal dominantly inherited connective tissue disorder, mostly caused by mutations in the fibrillin-1 (FBN1) gene. We, by using targeted next-generation sequence analysis, identified a novel intronic FBN1 mutation (the c.2678-15C>A variant) in a MFS patient with aortic dilatation. The computational predictions showed that the heterozygous c.2678-15C>A intronic variant might influence the splicing process by differentially affecting canonical versus cryptic splice site utilization within intron 22 of the FBN1 gene. RT-PCR and Western blot analyses, using FBN1 minigenes transfected into HeLa and COS-7 cells, revealed that the c.2678-15C>A variant disrupts normal splicing of intron 22 leading to aberrant 13-nt intron 22 inclusion, frameshift, and premature termination codon. Collectively, the results strongly suggest that the c.2678-15C>A variant could lead to haploinsufficiency of the FBN1 functional protein and structural connective tissue fragility in MFS complicated by aorta dilation, a finding that further expands on the genetic basis of aortic pathology.

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The impact of a 48-h fast on SIRT1 and GCN5 in human skeletal muscle

Applied Physiology Nutrition and Metabolism ◽

10.1139/apnm-2016-0130 ◽

2016 ◽

Vol 41 (9) ◽

pp. 953-962 ◽

Cited By ~ 1

Author(s):

Brittany A. Edgett ◽

Trisha D. Scribbans ◽

James P. Raleigh ◽

Jennifer B.L. Matusiak ◽

Kristen Boonstra ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Messenger Rna ◽

Animal Studies ◽

Human Skeletal Muscle ◽

Muscle Protein ◽

Peak Oxygen Uptake ◽

The Impact ◽

Whole Muscle ◽

Activation Status

The present study examined the impact of a 48 h fast on the expression and activation status of SIRT1 and GCN5, the relationship between SIRT1/GCN5 and the gene expression of PGC-1α, and the PGC-1α target PDK4 in the skeletal muscle of 10 lean healthy men (age, 22.0 ± 1.5 years; peak oxygen uptake, 47.2 ± 6.7 mL/(min·kg)). Muscle biopsies and blood samples were collected 1 h postprandial (Fed) and following 48 h of fasting (Fasted). Plasma insulin (Fed, 80.8 ± 47.9 pmol/L; Fasted, not detected) and glucose (Fed, 4.36 ± 0.86; Fasted, 3.74 ± 0.25 mmol/L, p = 0.08) decreased, confirming participant adherence to fasting. Gene expression of PGC-1α decreased (p < 0.05, –24%), while SIRT1 and PDK4 increased (p < 0.05, +11% and +1023%, respectively), and GCN5 remained unchanged. No changes were observed for whole-muscle protein expression of SIRT1, GCN5, PGC-1α, or COX IV. Phosphorylation of SIRT1, AMPKα, ACC, p38 MAPK, and PKA substrates as well as nuclear acetylation status was also unaltered. Additionally, nuclear SIRT1 activity, GCN5, and PGC-1α content remained unchanged. Preliminary findings derived from regression analysis demonstrate that changes in nuclear GCN5 and SIRT1 activity/phosphorylation may contribute to the control of PGC-1α, but not PDK4, messenger RNA expression following fasting. Collectively, and in contrast with previous animal studies, our data are inconsistent with the altered activation status of SIRT1 and GCN5 in response to 48 h of fasting in human skeletal muscle.

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The transcriptomic blueprint of molt in rooster using various tissues from Ginkkoridak (Korean long-tailed chicken)

BMC Genomics ◽

10.1186/s12864-021-07903-9 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Clémentine Charton ◽

Dong-Jae Youm ◽

Byung June Ko ◽

Donghyeok Seol ◽

Bongsang Kim ◽

...

Keyword(s):

Gene Expression ◽

Nervous System ◽

Messenger Rna ◽

Ribosomal Proteins ◽

Reproductive Tract ◽

Gene Transcript ◽

Cell Dynamics ◽

Tissue Samples ◽

Physiological Functions ◽

The Impact

Abstract Background Annual molt is a critical stage in the life cycle of birds. Although the most extensively documented aspects of molt are the renewing of plumage and the remodeling of the reproductive tract in laying hens, in chicken, molt deeply affects various tissues and physiological functions. However, with exception of the reproductive tract, the effect of molt on gene expression across the tissues known to be affected by molt has to date never been investigated. The present study aimed to decipher the transcriptomic effects of molt in Ginkkoridak, a Korean long-tailed chicken. Messenger RNA data available across 24 types of tissue samples (9 males) and a combination of mRNA and miRNA data on 10 males and 10 females blood were used. Results The impact of molt on gene expression and gene transcript usage appeared to vary substantially across tissues types in terms of histological entities or physiological functions particularly related to nervous system. Blood was the tissue most affected by molt in terms of differentially expressed genes in both sexes, closely followed by meninges, bone marrow and heart. The effect of molt in blood appeared to differ between males and females, with a more than fivefold difference in the number of down-regulated genes between both sexes. The blueprint of molt in roosters appeared to be specific to tissues or group of tissues, with relatively few genes replicating extensively across tissues, excepted for the spliceosome genes (U1, U4) and the ribosomal proteins (RPL21, RPL23). By integrating miRNA and mRNA data, when chickens molt, potential roles of miRNA were discovered such as regulation of neurogenesis, regulation of immunity and development of various organs. Furthermore, reliable candidate biomarkers of molt were found, which are related to cell dynamics, nervous system or immunity, processes or functions that have been shown to be extensively modulated in response to molt. Conclusions Our results provide a comprehensive description at the scale of the whole organism deciphering the effects of molt on the transcriptome in chicken. Also, the conclusion of this study can be used as a valuable resource in transcriptome analyses of chicken in the future and provide new insights related to molt.

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Identification of FBN1 gene mutations in Ukrainian Marfan syndrome patients

Genetics Research ◽

10.1017/s0016672316000112 ◽

2016 ◽

Vol 98 ◽

Cited By ~ 1

Author(s):

RUSTAM ZHURAYEV ◽

DORIEN PROOST ◽

DMYTRO ZERBINO ◽

VIKTOR FEDORENKO ◽

JOSEPHINA A. N. MEESTER ◽

...

Keyword(s):

Genetic Testing ◽

Marfan Syndrome ◽

Aortic Surgery ◽

Gene Mutations ◽

Cardiovascular Complications ◽

Connective Tissue Disorder ◽

Targeted Next Generation Sequencing ◽

Fbn1 Gene ◽

Significant Difference ◽

Life Threatening

SummaryMarfan syndrome is an autosomal dominant connective tissue disorder, predominantly affecting the ocular, skeletal and cardiovascular systems. Here, we present the results of the first genetic testing in 40 Ukrainian Marfan (-like) patients and 10 relatives. We applied a targeted next generation sequencing panel comprising FBN1 and 13 thoracic aortic aneurysm genes. We identified 27 causal mutations in FBN1, obtaining a mutation yield of 67·5%. A significant difference in age at aortic surgery between mutation positive and negative patients was observed. Thus, we conclude that genetic testing is important to identify patients at higher risk for developing life-threatening cardiovascular complications.

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