PhD position: Molecular dynamics of phase separation-controlled gene transcription

Molecular dynamics of phase separation-controlled gene transcription

Acute myeloid leukemia (AML) is a genetic disease in which gene mutations 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 intrinsically disordered leukemic oncogenes might 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 we aim to discover how these oncogenic TCs are formed and mis-regulate gene transcription. The overarching aim of this project, using molecular dynamics simulations, 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.

Requested skills: We look for a candidate with a master’s degree in (bio)physics, (bio)chemistry or a related field, with a strong interest in molecular dynamics simulations. 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. We expect excellent writing and speaking/presentation skills in English. This project will be carried out in close collaboration with an experimental PhD student that will start at the same time, so good team working skills are required.

What we offer:

- full-time contract for 4 years

- a monthly salary of €  2901 gross in the first year to a maximum of € 3707 gross per month in the final year (PhD salary scale), based on a full-time position

- a holiday allowance of 8% gross annual income and an 8.3% year-end bonus

- preferred starting date in summer 2025

Contact: For more information, please send your CV to Prof.dr.ir. P.R. Onck (p.r.onck@rug.nl or http://www.rug.nl/staff/p.r.onck/index).