PhD student: Phase separation-controlled gene transcription in leukemia Groningen • UMC Groningen

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We are looking for two talented and enthusiastic PhD students to work on a recently awarded ZonMW Open Competition project grant entitled “Phase separation-controlled gene transcription in leukemia”. This is a collaborative project between the Department of Experimental Hematology at the University Medical center Groningen (led by prof.dr. J.J. Schuringa) and the Zernike Institute for Advanced materials at the University of Groningen (led by prof.dr. P.R. Onck). The general aims of the division of Experimental Hematology are to obtain detailed knowledge on (molecular) mechanisms that determine hematopoietic stem cell self-renewal and differentiation, with the ultimate goal to deepen our insights in the development of human leukemias. We specifically aim to unravel gene transcription and epigenetic mechanisms that drive leukemic transformation. The Onck group has expertise in multiscale computational modelling, aimed at bridging the gap between the atomistic and (supra)molecular length scales. Studies focus on uncovering the fundamental molecular mechanisms of a wide range of fascinating biological systems such as cytoskeletal protein networks, viral fusion proteins, cilia and nuclear pore complexes. The lab has built a strong track record in all-atom and coarse-grained (CG) molecular dynamics (MD) approaches to model intrinsically disordered proteins (IDPs), which will also be relevant for the current project.

Acute myeloid leukemia (AML) is a somatic genetic disease in which gene mutations or chromosomal translocations accumulate in hematopoietic stem cells thereby disturbing normal blood cell development. AML is extremely difficult to treat, and better treatment options are urgently needed. AML mutations are typically found in a broad range of signaling molecules resulting in aberrant transcriptional programs that drive leukemic transformation. A better understanding of derailed signaling in AML patients is key to developing more effective treatment strategies. Recent findings indicate that transcription is not only a biochemical, but also a biophysical process: spatial localization plays a key role during which all transcriptional components, promoters and enhancers are brought together in so-called transcriptional condensates (TCs), assemblies formed by the propensity of various transcriptional regulators to phase separate at the chromatin. The biophysical process of phase separation is predominantly driven by proteins that are intrinsically disordered (IDPs), i.e., do not have a clear predefined structure. We and others have recently identified that several leukemic oncogenes are also intrinsically disordered and might therefore be initiators of the formation of TCs through phase separation. These exciting observations bring together the biophysical mechanism of phase separation and the cell-biological process of oncogenic transcription. In this proposal two experts with strong complementary expertise in these separate fields join forces to discover how these oncogenic TCs are formed and mis-regulate gene transcription. The overarching aim of this application, using both computational approaches and multi-omics wet lab experimentation, is to develop a comprehensive roadmap of leukemic IDPs, unravel the composition and function of phase separation-controlled leukemic transcriptional condensates, and investigate whether interfering with their function and/or formation will provide alternative treatment strategies for patients with AML. We anticipate that our studies will not only provide important fundamental insights but also provide better therapeutic options for AML patients. For further information please contact: prof.dr. J.J.Schuringa () or prof.dr. P.R. Onck ().

Project 1: Cell biological/molecular studies to better understand phase separation-controlled gene transcription in leukemia

• required education: Master’s degree in biomedical/life sciences-related subject.
• experience in cell biological techniques (e.g. eukaryotic tissue culture) is required.
• expertise with molecular biology techniques is a pre (e.g. in molecular cloning, CRISPR/CAS9 gene editing, protein expression).
• excellent writing and speaking/presentation skills in English.
• you are enthusiastic, ambitious and are a team player.

Project 2: Computational modeling studies to better understand phase separation-controlled gene transcription in leukemia

• required education: Master’s degree in biomedical/life-sciences, (bio)physics, (bio)chemistry or a related field.
• candidates should have a strong interest in computational modelling.
• the project will entail programming (scripting, Python etc.), handling big data and carrying out all-atom and coarse-grained molecular dynamics simulations on high-performance super-computers.
• excellent writing and speaking/presentation skills in English.
• you are enthusiastic, ambitious and are a team player.

A full-time appointment for four years (36 hours a week). Your salary will be a maximum of € 3.824 gross per month (scale PRO), depending on your qualifications and relevant experience, based on a full-time appointment. Additionally, the UMCG offers an 8% holiday allowance, an 8.3% year-end bonus.The conditions of employment comply with the Collective Labour Agreement for Medical Centres (CAO-UMC). The position offered is for four years. First, a temporary one-year position will be offered with the option of renewal for another three years. Extension of the contract will be based on sufficient progress and the expectation of a successful completion of the PhD project in the next three years.

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