Helmholtz Postdoc Programme

Overcoming Epigenetic Barriers for Reprogramming Cells

 

Successful cell replacement therapies for Alzheimer’s, Diabetes and Parkinson diseases aim to replace lost cell types by introducing the necessary cell types into the damaged tissues. One way to generate desired cell types involves reprogramming of available cell types into a stem cell-like state called iPS (induced Pluripotent Stem) cells using a cocktail of transcription factors. iPS cells can be, in principle, subsequently re-differentiated into any cell types as proven through generation of mice from iPS cells. However, therapeutic use of iPS cells might bear risks such as introduction of mutations or teratoma formation. Alternatively, direct cell fate conversion produces the desired cell types by skipping the initial step of generating proliferative pluripotent cells. However, many cells display resistance to be reprogrammed directly into other cell types probably due to the absence of “co-activators” or presence of “inhibitory factors” required for cell reprogramming.

 

Reverse and forward genetics screens conducted by Dr. Baris Tursun on C. elegans have successfully uncovered numerous “inhibitory factors”. Depletion of LIN-53 (mammalian RBBP4/7) and components of the Polycomb Repressive Complex 2 results in germ cells to be reprogrammed, confirming the concept of inhibitory mechanisms that restrict reprogramming of cell fates. We propose to conduct forward genetics screens coupled with biochemical analysis to dissect molecular and biochemical mechanisms behind cell plasticity. We believe that genome wide screening will provide conserved molecular profiles for specific cell type conversion, which we hope will apply to mammals and thereby provide valuable knowledge for the field of tissue replacement therapies in the future.