3D Modeling of the interactions of the lncRNA ANRIL with DNA and proteins in epigenetic regulation
Keywords: Molecular modeling, Computational biophysics, structural bioinformatics, RNA-protein interactions, docking, binding energy computation, molecular dynamics simulation
Employer: INRIA Grand-Est (LORIA lab, Lorraine University – CNRS – INRIA ), Nancy, France
Contact: Dr. Isaure Chauvot de Beauchene (isaure.chauvot-de-beauchene (at) loria.fr)
Start: early 2020
Duration: 1st period of 10 months, renewable.
The research of the CAPSID team at the LORIA lab combines aspects of various disciplines : biophysics, structural biology, and algorithmic related to 3D coordinates, graphs, clustering and machine learning. In particular, we develop computational methods and tools to build 3D atomic representations of nucleic acids bound to proteins, with a focus on ssRNA (see references here). This Postdoc subject is part of the collaborative project interANRIL (coord. Sylvain Maenner) with the biology team RNA-RNP Eq1 at the IMoPA lab.
In humans, the long non-coding RNA (lncRNA) ANRIL is an important factor of susceptibility to cardiovascular diseases. It is involved in the epigenetic regulation of the expression of a network of genes, via mechanisms that are still largely unknown. This project aims to model the protein-RNA and / or DNA-RNA interactions that ANRIL establishes within the eukaryotic genome. lncRNA can bind DNA via two main processes: (i) by binding to RNA-binding proteins (“RBP”) that bind in turn the DNA, or (ii) by the direct formation of DNA-RNA triple-helices (“triplexes”). Our partner has already experimentally identified (i) the main RBP partner of ANRIL and (ii) genomic loci directly contacted by ANRIL, and a reccurent DNA motif at these loci that is compatible with triplexes formation.
1/ 3D modeling of ANRIL-ADN triplexes
ANRIL ssRNA motifs and the DNA motifs of the loci identified as ANRIL targets will be combined in triplex models, based on the triplex crystallographic structures available in the PDB and on the nucleic acid modeling tools developed by the CAPSID team at LORIA.
The relative stability of these triplexes will be evaluated by molecular dynamics simulation (access to the Grid’5000 cluster), then the most probable stable triplexes will be identified by binding energy calculations. This study will serve as a basis for the development of oligonucleotides as competitors of ANRIL-DNA interactions.
2/ 3D modelling of ANRIL-protein interactions
ANRIL main protein partner has been crystallized in complex with DNA sequences. These structures will serve as a basis for the modelling of ANRIL-protein interactions, their study by molecular dynamics and their quantitative evaluation by binding energy calculations.
- literature monitoring on methods for prediction and modelling of RNA-DNA triplexes and protein-ssRNA complexes
- literature monitoring on ANRIL and other lncRNA
- development of a pipeline for modelling triplexes of a given sequence
- modelling, simulation and analysis of ANRIL-DNA and ANRIL-protein systems
- writing publications
- Collaboration with two PhD students on RRM-ssRNA interaction modeling for the design of RNA-binding proteins.
- Co-supervision of trainees.
- Teaching in bioinformatics
Candidates must have (or be about to get) a PhD degree in any of the relevant disciplines: bio-physics, bio-informatics, chemo-informatics or structural biology.
The thesis must have been defended after September 1st, 2017
The candidate must have experience in molecular modeling.
Good scripting and programming skills (preferentially Python) are required.
Candidates must be fluent in English.
INRIA Post-doc contract.
Applications should be sent in PDF format and must include:
- a detailed recent CV
- a list of publications
- a cover letter describing the candidate’s research interest and expertise relevant to the subject
- the name of at least 3 scientists willing to provide a letter of recommendation, incl. Master supervisor and PhD supervisor.
- the thesis reports if available
- links to the Master/PhD thesis if available