Postdoctoral Fellowship: RNA in cardiovascular diseases
The Lorraine University of Excellence Program is inviting applications for a post-doctoral position (100%, 24 months) on the role of RNAs in cardiovascular diseases and their possible use as predictive biomarkers within the “Geenage” IMPACT project (Functional Genomics, Epigenomics and Environmental interplay to IMPACT the understanding, diagnosis and management of healthy and pathological AGEing”).
LUE IMPACT GEENAGE. The ambition of GEENAGE is to produce new strategies of diagnosis and management of healthy and pathological ageing by targeting the functional consequences of the interplay between genes, epigenome and environment.
Duration: 24 months post-doctoral position available
General concept and contribution of our research group:
Cardiovascular diseases are major cause of hospitalization and death. The present conditions of life and the increase of life span reinforce the burden they represent for industrialized societies. Our goal is to develop new diagnosis for early detection and therefore for prevention of heart failure. Several types of RNAs were shown to play a role in human pathologies, including cardiovascular diseases. This is the case for: (i) miRNAs with regulatory roles in both transcriptional and translational processes, (ii) long non-coding RNAs that regulate chromatin organization and gene expression, (iii) alternative exons in mRNAs that are generated by alternative splicing of primary polymerase II transcripts and are leading to the production of alternative proteins. As these various types of RNAs are found in blood they can be used as predictive biomarkers using non-invasive analytic methods.
The host team (including Dr C Branlant, Pr I Motorin and Dr I Behm-Ansmant) is a CNRS-Lorraine University internationally recognized team in the field of RNA structure and function. The post-doctoral project will be developed in the frame of a strong collaboration between this research team from the Biopôle Institute of Lorraine University and an INSERM-Lorraine University cardiology research team including physicians from the Nancy CHRU. It will benefit from the high standard platforms of the Biopôle Institute (Next Generation Sequencing, Cell biology, Structural biology, Microscopy). It will also benefit from the Stanislas longitudinal cohort established 25 years ago in Lorraine. This cohort is managed by the cardiology team (headed by Prs F Zannad and P Rossignol), which is also sharing several other cohorts with European teams in the frame of H2020 European projects. The proposed post-doctoral project is based on the following general concept: some of the blood circulating RNAs can be indicative of the risk of future cardiac heart failure especially they can be predictive of early steps in left ventricular hypertrophy and/or subclinical atherosclerosis.
The longitudinal and familial Stanislas cohort (clinicaltrials.gov: NCT01391442) established in 1993 with volunteers from Lorraine area without chronic or acute disorders and previous personal cardiac history (1006 families – including 2 parents and 2 children – with available follow up every 4-5 years). At the 4th visit follow up, extensive cardiovascular phenotyping were performed by the INSERM clinician team. Almost 40% of the subjects aged 50 years and more were identified as being at stage B Heart Failure (asymptomatic structural abnormalities) by echo-cardiography. Almost 30% of the subjects had a carotid intima media thickness value above the expected value for their age (indication of subclinical atherosclerosis). We expect the presence of putative RNA biomarkers of these pathologies in the plasma, total blood or PBMC fractions collected at the 4th visit. We hypothesize that the characterization of complete blood RNA or PBMC transcriptomes by deep sequencing and micro-array analyses will allow the identification of such predictive RNA biomarkers
Objective and organization of the research:
Total RNAs were already prepared from PBMCs of 715 members of the Stanislas cohort. According to clinical investigations, members were classified into two groups: with or without left ventricular hypertrophy (LVH). Members of each group were paired according to the sex, the age, and the BMI and total RNA from PBMCs were subjected to deep sequencing. Data from 45 members with and 45 members without LVH were compared (global level of gene expression and level of alternative splicing products including for lncRNAs) leading to the selection of some putative biomarkers which validation is undergoing.
The candidate will continue this study and extend it to other members of the cohort using both deep-sequencing and Affymetrix microarrays dedicated to alternative splicing and non-coding RNA analyses. The validity of the selected putative RNA biomarkers will be assessed by RT-qPCR on a large number of members of the Stanislas cohort and on members of other well characterized cohorts. The clinical validation of potential RNA markers will consist to test the superiority of these new biomarkers over existing individual classical non-RNA based biomarkers as well as over risk models based on clinical variables. This part of the work will be performed in collaboration with statisticians from the clinical team and bioinformaticians from the INRIA-CNRS Bioinformatic Institute of Nancy also involved in the Geenage project.
The biological significance of the selected markers and their possible biological roles will be investigated by the use of different cell lines: cardiac fibroblast, vascular smooth muscle cells, HEK cells, …, and if possible on animal models through collaborations.
The Molecular Biology team, includes 2 CNRS scientists, 1 Professor, 1 Assistant Professor, 2 engineers, 1 postdoctoral fellow, 1 PhD student; the Cardiology team includes 3 Physician Professors, 2 clinical assistants, 2 data managers, 4 biostatisticians, 2 engineers/technicians, 1 study coordinator and 2 research nurses.
Major publications of the group in this topic:
– Weldon C, Dacanay JG, Gokhale V, Boddupally PVL, Behm-Ansmant I, Burley GA, Branlant C, Hurley LH, Dominguez C, Eperon IC. Specific G-quadruplex ligands modulate the alternative splicing of Bcl-X. Nucleic Acids Res. 2018 Jan 25;46(2):886-896.
– Guéant JL, Chéry C, Oussalah A, Nadaf J, Coelho D, Josse T, Flayac J, Robert A, Koscinski I, Gastin I, Filhine-Tresarrieu P, Pupavac M, Brebner A, Watkins D, Pastinen T, Montpetit A, Hariri F, Tregouët D, Raby BA, Chung WK, Morange PE, Froese DS, Baumgartner MR, Benoist JF, Ficicioglu C, Marchand V, Motorin Y, Bonnemains C, Feillet F, Majewski J, Rosenblatt DS. A PRDX1 mutant allele causes a MMACHC secondary epimutation in cblC patients. Nat Commun. 2018 Jan 4;9(1):67
– Aschenbrenner J, Werner S, Marchand V, Adam M, Motorin Y, Helm M, Marx A. Engineering of a DNA Polymerase for Direct m6 A Sequencing. Angew Chem Int Ed Engl. 2018 Jan 8;57(2):417-421.
– Erales J, Marchand V, Panthu B, Gillot S, Belin S, Ghayad SE, Garcia M, Laforêts F, Marcel V, Baudin-Baillieu A, Bertin P, Couté Y, Adrait A, Meyer M, Therizols G, Yusupov M, Namy O, Ohlmann T, Motorin Y, Catez F, Diaz JJ. Evidence for rRNA 2′-O-methylation plasticity: Control of intrinsic translational capabilities of human ribosomes. Proc Natl Acad Sci U S A. 2017 Dec 5;114(49):12934-12939.
– Moulin D, Salone V, Koufany M, Clément T, Behm-Ansmant I, Branlant C, Charpentier B, Jouzeau JY. MicroRNA-29b Contributes to Collagens Imbalance in Human Osteoarthritic and Dedifferentiated Articular Chondrocytes. Biomed Res Int. 2017;2017:9792512.
– Rothé B, Manival X, Rolland N, Charron C, Senty-Ségault V, Branlant C, Charpentier B. Implication of the box C/D snoRNP assembly factor Rsa1p in U3 snoRNP assembly. Nucleic Acids Res. 2017 Jul 7;45(12):7455-7473.
– Weldon C, Behm-Ansmant I, Hurley LH, Burley GA, Branlant C, Eperon IC, Dominguez C. Identification of G-quadruplexes in long functional RNAs using 7-deazaguanine RNA. Nat Chem Biol. 2017 Jan;13(1):18-20.
– Vautrot V, Aigueperse C, Oillo-Blanloeil F, Hupont S, Stevenin J, Branlant C, Behm-Ansmant I. Enhanced SRSF5 Protein Expression Reinforces Lamin A mRNA Production in HeLa Cells and Fibroblasts of Progeria Patients. Hum Mutat. 2016 Mar;37(3):280-91.
– Bizarro J, Dodré M, Huttin A, Charpentier B, Schlotter F, Branlant C, Verheggen C, Massenet S, Bertrand E. NUFIP and the HSP90/R2TP chaperone bind the SMN complex and facilitate assembly of U4-specific proteins. Nucleic Acids Res. 2015 Oct 15;43(18):8973-89.
– Carpentier C, Ghanem D, Fernandez-Gomez FJ, Jumeau F, Philippe JV, Freyermuth F, Labudeck A, Eddarkaoui S, Dhaenens CM, Holt I, Behm-Ansmant I, Marmier-Gourrier N, Branlant C, Charlet-Berguerand N, Marie J, Schraen-Maschke S, Buée L, Sergeant N, Caillet-Boudin ML. Tau exon 2 responsive elements deregulated in myotonic dystrophy type I are proximal to exon 2 and synergistically regulated by MBNL1 and MBNL2. Biochim Biophys Acta. 2014 Apr;1842(4):654-64.
Bizarro J, Charron C, Boulon S, Westman B, Pradet-Balade B, Vandermoere F, Chagot ME, Hallais M, Ahmad Y, Leonhardt H, Lamond A, Manival X, Branlant C, Charpentier B, Verheggen C, Bertrand E. Proteomic and 3D structure analyses highlight the C/D box snoRNP assembly mechanism and its control. J Cell Biol. 2014 Nov 24;207(4):463-80.
– Rothé B, Back R, Quinternet M, Bizarro J, Robert MC, Blaud M, Romier C, Manival X, Charpentier B, Bertrand E, Branlant C. Characterization of the interaction between protein Snu13p/15.5K and the Rsa1p/NUFIP factor and demonstration of its functional importance for snoRNP assembly. Nucleic Acids Res. 2014 Feb;42(3):2015-36.
– Lopez-Mejia IC, Vautrot V, De Toledo M, Behm-Ansmant I, Bourgeois CF, Navarro CL, Osorio FG, Freije JM, Stévenin J, De Sandre-Giovannoli A, Lopez-Otin C, Lévy N, Branlant C, Tazi J. A conserved splicing mechanism of the LMNA gene controls premature aging. Hum Mol Genet. 2011 Dec 1;20(23):4540-55.
– Tran H, Gourrier N, Lemercier-Neuillet C, Dhaenens CM, Vautrin A, Fernandez-Gomez FJ, Arandel L, Carpentier C, Obriot H, Eddarkaoui S, Delattre L, Van Brussels E, Holt I, Morris GE, Sablonnière B, Buée L, Charlet-Berguerand N, Schraen-Maschke S, Furling D, Behm-Ansmant I, Branlant C, Caillet-Boudin ML, Sergeant N. Analysis of exonic regions involved in nuclear localization, splicing activity, and dimerization of Muscleblind-like-1 isoforms. J Biol Chem. 2011 May 6;286(18):16435-46.
– Ferreira JP, Girerd N, Gregson J, Latar I, Sharma A, Pfeffer MA, McMurray JJV, Abdul-Rahim AH, Pitt B, Dickstein K, Rossignol P, Zannad F; High-Risk Myocardial Infarction Database Initiative. Stroke Risk in Patients With Reduced Ejection Fraction After Myocardial Infarction Without Atrial Fibrillation. J Am Coll Cardiol. 2018 Feb 20;71(7):727-735.
– Ferreira JP, Duarte K, Pfeffer MA, McMurray JJV, Pitt B, Dickstein K, Zannad F, Rossignol P; High-Risk Myocardial Infarction Database Initiative. Association between mean systolic and diastolic blood pressure throughout the follow-up and cardiovascular events in acute myocardial infarction patients with systolic dysfunction and/or heart failure: an analysis from the High-Risk Myocardial Infarction Database Initiative. Eur J Heart Fail. 2018 Feb;20(2):323-331.
– Ferreira JP, Girerd N, Bozec E, Mercklé L, Pizard A, Bouali S, Eby E, Leroy C, Machu JL, Boivin JM, Lamiral Z, Rossignol P, Zannad F. Cohort Profile: Rationale and design of the fourth visit of the STANISLAS Cohort: a familial longitudinal population-based cohort from the Nancy region of France. Int J Epidemiol. 2017 Dec 6.
– Girerd N, Seronde MF, Coiro S, Chouihed T, Bilbault P, Braun F, Kenizou D, Maillier B, Nazeyrollas P, Roul G, Fillieux L, Abraham WT, Januzzi J, Sebbag L, Zannad F, Mebazaa A, Rossignol P; INI-CRCT, Great Network, and the EF-HF Group. Integrative Assessment of Congestion in Heart Failure Throughout the Patient Journey. JACC Heart Fail. 2017 Dec 6. pii: S2213-1779(17)30688-1.
Núñez J, Bayés-Genís A, Zannad F, Rossignol P, Núñez E, Bodí V, Miñana G, Santas E, Chorro FJ, Mollar A, Carratalá A, Navarro J, Gorriz JL, Lupón J, Husser O, Metra M, Sanchis J. Long-Term Potassium Monitoring and Dynamics in Heart Failure and Risk of Mortality. Circulation. 2017 Oct 12.
– Ferreira JP, Girerd N, Bozec E, Machu JL, Boivin JM, London GM, Zannad F, Rossignol P.
Intima-Media Thickness Is Linearly and Continuously Associated With Systolic Blood Pressure in a Population-Based Cohort (STANISLAS Cohort Study). J Am Heart Assoc. 2016 Jun 16;5(6).
– Frikha Z, Girerd N, Huttin O, Courand PY, Bozec E, Olivier A, Lamiral Z, Zannad F, Rossignol P. Reproducibility in echocardiographic assessment of diastolic function in a population based study (the STANISLAS Cohort study). PLoS One. 2015 Apr 8;10(4):e0122336.
– Huttin O, Fraser AG, Coiro S, Bozec E, Selton-Suty C, Lamiral Z, Frikha Z, Rossignol P, Zannad F, Girerd N. Impact of Changes in Consensus Diagnostic Recommendations on the Echocardiographic Prevalence of Diastolic Dysfunction. J Am Coll Cardiol. 2017 Jun 27;69(25):3119-3121.
The applicant should be familiar with molecular biology concepts. He/she should have a strong expertise in the field of nucleic acids (concepts and methodologies: RNA extraction, manipulation, sequencing, QRTPCR) and in animal cell culture, cell fractionation.
Expertise in the interpretation of high throughput sequencing or microarray data as well as in the field of cardiovascular diseases would be appreciated.
Applicants should be able to conduct his/her research independently but also to work in a team.
TERMS AND TENURE
This 24 months post-doctoral fellow will develop his/her experimental research at the IMoPA research laboratory (CNRS-UL UMR7365, Biopôle of the Lorraine University, Vandoeuvre-les-Nancy, France).
The target start date for the position is [June 2018], with some flexibility.
HOW TO APPLY
Applicants are requested to submit the following materials:
• A cover letter applying for the position
• Full CV and list of publications
• Academic transcripts
- Reference letters from PhD/postdoc supervisors
Deadline for application is April 15 2018. Applicants will be interviewed by an Ad Hoc Commission by [day to define in April].
Applications have to be sent through email to Dr Isabelle Behm-Ansmant, PhD, email@example.com
CNRS-UL UMR 7365, Vandœuvre-lès-Nancy, Université de Lorraine, France.
- Curriculum Vitae – Your most recently updated C.V. including list of publications
- Cover Letter
- Statement of Research
- Reference letters