19 research outputs found
Understanding the transcriptional control of EIF4E and its dysregulation in acute myeloid leukemia: role of NF-ÎșB
EIF4E, le facteur dâinitiation de la traduction chez les eucaryotes est un oncogĂšne puissant et qui se trouve induit dans plusieurs types de cancers, parmi lesquels les sous-types M4 et M5 de la leucĂ©mie aiguĂ« myĂ©loblastique (LAM). EIF4E est rĂ©gulĂ© Ă plusieurs niveaux cependant, la rĂ©gulation transcriptionnelle de ce gĂšne est peu connue. Mes rĂ©sultats montrent que EIF4E est une cible transcriptionnelle directe du facteur nuclĂ©aire « kappa-light- chain- enhancer of activated B cells » (NF-ÎșB).Dans les cellules hĂ©matopoĂŻĂ©tiques primaires et les lignĂ©es cellulaires, les niveaux de EIF4E sont induits par des inducteurs de NF-ÎșB. En effet, lâinactivation pharmaceutique ou gĂ©nĂ©tique de NF-ÎșB rĂ©prime lâactivation de EIF4E. En effet, suite Ă lâactivation de NF-ÎșB chez lâhumain, le promoteur endogĂšne de EIF4E recrute p65 (RelA) et c-Rel aux sites Ă©volutionnaires conservĂ©s ÎșB in vitro et in vivo en mĂȘme temps que p300 ainsi que la forme phosphorylĂ©e de Pol II. De plus, p65 est sĂ©lectivement associĂ© au promoteur de EIF4E dans les sous-types LAM M4/M5 mais non pas dans les autres sous-types LAM ou dans les cellules hĂ©matopoĂŻĂ©tiques primaires normales. Ceci indique que ce processus reprĂ©sente un facteur essentiel qui dĂ©termine lâexpression diffĂ©rentielle de EIF4E dans la LAM. Les analyses de donnĂ©es dâexpressions par sĂ©quençage de lâARN provenant du « Cancer Genome Atlas » (TCGA) suggĂšrent que les niveaux dâARNm de EIF4E et RELA se trouvent augmentĂ©s dans les cas LAM Ă pronostic intermĂ©diaire ou faible mais non pas dans les groupes cytogĂ©nĂ©tiquement favorables. De plus, des niveaux Ă©levĂ©s dâARNm de EIF4E et RELA sont significativement associĂ©s avec un taux de survie relativement bas chez les patients. En effet, les sites uniques ÎșB se trouvant dans le promoteur de EIF4E recrutent le rĂ©gulateur de transcription NF-ÎșB p65 dans 47 nouvelles cibles prĂ©vues. Finalement, 6 nouveaux facteurs de transcription potentiellement impliquĂ©s dans la rĂ©gulation du gĂšne EIF4E ont Ă©tĂ© prĂ©dits par des analyses de donnĂ©es ChIP-Seq provenant de lâencyclopĂ©die des Ă©lĂ©ments dâADN (ENCODE). Collectivement, ces rĂ©sultats fournissent de nouveaux aperçus sur le control transcriptionnel de EIF4E et offrent une nouvelle base molĂ©culaire pour sa dĂ©rĂ©gulation dans au moins un sous-groupe de spĂ©cimens de LAM. LâĂ©tude et la comprĂ©hension de ce niveau de rĂ©gulation dans le contexte de spĂ©cimens de patients sâavĂšre important pour le dĂ©veloppement de nouvelles stratĂ©gies thĂ©rapeutiques ciblant lâexpression du gĂšne EIF4E moyennant des inhibiteurs de NF-ÎșB en combinaison avec la ribavirine.The eukaryotic translation initiation factor EIF4E is a powerful oncogene that is overexpressed in cancers, including the M4 and M5 subtypes of acute myeloid leukemia (AML). EIF4E is regulated at multiple levels; however not much is known about the transcriptional regulation of this gene. My findings show that the nuclear factor kappa-light- chain-enhancer of activated B cells (NF-ÎșB) is a direct transcriptional regulator of EIF4E. EIF4E levels are induced in primary hematopoietic cells and in cell lines in response to NF-ÎșB activating stimuli. Pharmacological and genetic inhibition of NF-ÎșB suppresses EIF4E levels. NF-ÎșB factors RelA (p65) and c-Rel are recruited to evolutionarily conserved ÎșB sites in the EIF4E promoter in vitro and in vivo following NF-ÎșB activation concurrent with the recruitment of p300 and phosphorylated Pol II. Furthermore, p65 is selectively associated with the EIF4E promoter in M4/M5 AML subtypes but not in other AML subtypes or normal primary hematopoietic cells and thus represents an underlying factor in determining the differential expression of EIF4E in AML. Analysis of gene expression RNA-Seq data from The Cancer Genome Atlas (TCGA) suggests that EIF4E and RELA mRNA levels are upregulated in intermediate and poor prognosis AML but not in the cytogenetically favorable group. Additionally, elevated EIF4E and RELA mRNA levels are significantly associated with worst patient survival outcome. Furthermore, 8 new putative NF-ÎșB target genes that may be regulated with a pattern similar to EIF4E in poor prognosis AML were in silico predicted from Chip-Seq data. Finally, 6 new transcription factors that may be implicated in EIF4E gene regulation were predicted from the analysis of ChIP-Seq data from the encyclopedia of DNA elements (ENCODE). Collectively, these findings could offer novel insights into the transcriptional regulation of EIF4E and a novel molecular basis for its dysregulation in AML. Understanding this level of regulation within the context of patient specimens is important for the development of novel therapeutic strategies to target EIF4E gene expression with specific NF-ÎșB inhibitors combined with ribavirin
Publisher Correction: A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients
The original version of this Article contained an error in the title, which was incorrectly given as 'APRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients'. This has now been corrected in both the PDF and HTML versions of the Article to read 'A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients'
A Novel Mutation in FOXC1 in a Lebanese Family with Congenital Heart Disease and Anterior Segment Dysgenesis: Potential Roles for NFATC1 and DPT in the Phenotypic Variations
Congenital heart diseases (CHDs) are still the leading cause of death in neonates. Anterior segment dysgenesis is a broad clinical phenotype that affects the normal development of the eye, leading in most of the cases to glaucoma which is still a major cause of blindness for children and adolescents. Despite tremendous insights gained from genetic studies, a clear genotypeâphenotype correlation is still difficult to draw. In Lebanon, a small country with still a high rate of consanguineous marriages, there are little data on the epidemiology of glaucoma amongst children with or without CHD. We carried out whole exome sequencing (WES) on a family with anterior segment dysgenesis, and CHD composed of three affected children with glaucoma, two of them with structural cardiac defects and three healthy siblings. The results unravel a novel mutation in FOXC1 (p. R127H) segregating with the phenotype and inherited from the mother, who did not develop glaucoma. We propose a digenic model for glaucoma in this family by combining the FOXC1 variant with a missense variant inherited from the father in the dermatopontin (DPT) gene. We also unravel a novel NFATC1 missense mutation predicted to be deleterious and present only in the patient with a severe ocular and cardiac phenotype. This is the first report on FOXC1 using WES to genetically characterize a family with both ocular and cardiac malformations. Our results support the usage of such technology to have a better genotypeâphenotype picture for Mendelian-inherited diseases for which expressivity and penetrance are still not answered
Recommended from our members
GATA5 mutation homozygosity linked to a double outlet right ventricle phenotype in a Lebanese patient
Abstract Background: GATA transcription factors are evolutionary conserved zinc finger proteins with multiple roles in cell differentiation/proliferation and organogenesis. GATA5 is only transiently expressed in the embryonic heart, and the inactivation of both Gata5 alleles results in a partially penetrant bicuspid aortic valve (BAV) phenotype in mice. We hypothesized that only biallelic mutations in GATA5 could be disease causing. Methods: A total of 185 patients with different forms of congenital heart disease (CHD) were screened along 150 healthy individuals for GATA4, 5, and 6. All patients' phenotypes were diagnosed with echocardiography. Results: Sequencing results revealed eight missense variants (three of which are novel) in cases with various conotruncal and septal defects. Out of these, two were inherited in recessive forms: the p.T67P variant, which was found both in patients and in healthy individuals, and the previously described p.Y142H variant which was only found in a patient with a double outlet right ventricle (DORV). We characterized the p.Y142H variant and showed that it significantly reduced the transcriptional activity of the protein over cardiac promoters by 30â40%. Conclusion: Our results do prove that p.Y142H is associated with DORV and suggests including GATA5 as a potential gene to be screened in patients with this phenotype
Genome-wide association study implicates immune dysfunction in the development of Hodgkin lymphoma
To further our understanding of inherited susceptibility to Hodgkin lymphoma (HL), we performed a meta-analysis of 7 genome-wide association studies totaling 5325 HL cases and 22â423 control patients. We identify 5 new HL risk loci at 6p21.31 (rs649775; P = 2.11 Ă 10â10), 6q23.3 (rs1002658; P = 2.97 Ă 10â8), 11q23.1 (rs7111520; P = 1.44 Ă 10â11), 16p11.2 (rs6565176; P = 4.00 Ă 10â8), and 20q13.12 (rs2425752; P = 2.01 Ă 10â8). Integration of gene expression, histone modification, and in situ promoter capture Hi-C data at the 5 new and 13 known risk loci implicates dysfunction of the germinal center reaction, disrupted T-cell differentiation and function, and constitutive NF-ÎșB activation as mechanisms of predisposition. These data provide further insights into the genetic susceptibility and biology of HL
Syndromic surveillance of respiratory-tract infections and hand hygiene practice among pilgrims attended Hajj in 2021: A cohort study
Background: This cohort study estimated the incidence of symptomatic respiratory tract infections (RTIs) and hand hygiene compliance with its impact among domestic Hajj pilgrims during the COVID-19 pandemic.
Methods: During the week of Hajj rituals in 2021, pilgrims were recruited by phone and asked to complete a baseline questionnaire. Pilgrims were followed up after seven days using a questionnaire about the development of symptoms, and practices of hand hygiene. Syndromic definitions were used to clinically diagnose âpossibleâ influenza-like illnesses (ILI) and COVID-19 infection.
Results: A total of 510 pilgrims aged between 18 and 69 (median of 50) years completed the questionnaire, 280 (54.9%) of whom were female, and all of them (except for one) were vaccinated against COVID-19 with at least one dose. The mean (±SD) of pilgrimsâ hand hygiene knowledge score (on a scale of 0 to 6) was 4.15 (±1.22), and a higher level of knowledge was correlated with a higher frequency of handwashing using soap and water. Among those 445 pilgrims who completed the follow-up form, 21 (4.7%) developed one or more respiratory symptoms, of which sore throat and cough were the commonest (respectively 76.2% and 42.8%); âpossible ILIâ and âpossible COVID-19â were present in 1.1% and 0.9% of pilgrims. Obesity was found to be a significant factor associated with the risk of developing RTIs (odds ratio = 4.45, 95% confidence interval 1.15â17.13).
Conclusion: Hajj pilgrims are still at risk of respiratory infections. Further larger and controlled investigations are needed to assess the efficacy of hand hygiene during Hajj
Recommended from our members
Genome-wide association study implicates immune dysfunction in the development of Hodgkin lymphoma.
To further our understanding of inherited susceptibility to Hodgkin lymphoma (HL), we performed a meta-analysis of seven genome-wide association studies totalling 5,325 HL cases and 22,423 controls. We identify five new HL risk loci at 6p21.31 (rs649775, P = 2.11 Ă 10-10), 6q23.3 (rs1002658, P = 2.97 Ă 10-8), 11q23.1 (rs7111520, P = 1.44 Ă 10-11), 16p11.2 (rs6565176, P = 4.00 Ă 10-8) and 20q13.12 (rs2425752, P = 2.01 Ă 10-8). Integration of gene expression, histone modification and in situ promoter capture Hi-C data at the five new and 13 known risk loci implicates dysfunction of the germinal centre reaction, disrupted T-cell differentiation and function, and constitutive NF-ÎșB activation as mechanisms of predisposition. These data provide further insights into the genetic susceptibility and biology of HL.Includes Bloodwise, Wellcome Trust and CRU
Comparative Assessment of Antimicrobial Efficacy of Seven Surface Disinfectants against Eight Bacterial Strains in Saudi Arabia: An In Vitro Study
Environmental conditions in hospitals facilitate the growth and spread of pathogenic bacteria on surfaces such as floors, bed rails, air ventilation units, and mobile elements. These pathogens may be eliminated with proper disinfecting processes, including the use of appropriate surface disinfectants. In this study, we aimed to evaluate of the antibacterial effects of seven surface disinfectants (HAMAYA, DAC, AJAX, Jif, Mr. MUSCLE, CLOROX, and BACTIL) against eight bacterial strains Klebsiella pneumoniae, Enterobacter aerogenes, Acinetobacter baumannii, Serratia marcescens, Escherichia coli, vancomycin-resistant Enterococcus faecalis-ATCC 51299, methicillin-resistant Staphylococcus aureus-ATCC 43300, and Pseudomonas aeruginosa-ATCC 1544, using two methods. The first was to determine the effective contact time of disinfectant against the tested bacterial strains, and the second was an assessment of the disinfection efficacy of each disinfectant on six types of contaminated surfaces with on a mixture of the eight tested bacterial strains. The results showed the efficacy of the disinfectants against the tested strains depending on the effective contact time. BACTIL disinfectant showed an efficacy of 100% against all tested strains at the end of the first minute of contact time. HAMAYA, DAC, Jif, Mr. MUSCLE, and CLOROX showed 100% efficiency at the end of the fourth, fifth, sixth, seventh, and fourteenth minutes, respectively, while AJAX disinfectant required nineteen minutes of contact time to show 100% efficacy against all tested strains