This week, international group of researchers described a new algorithm for identification of transcription factors, used in direct cell reprogramming. This is freely available computational tool, called Mogrify. This tool will allow to save a lot of time in finding the right transcription factor for conversion of one cell type to another. Before it was done by guess (well, gene profiling) and experimental confirmation of the best guess. Now it could be done by few clicks on a web-site and, again… experimental confirmation. This quote (edited) illustrates the scale of possible combinations to check in search of right transcription factor(s):
With roughly 2,000 different transcription factors and approximately 400 unique cell types in humans, the space of possible sets is very large (>1011 combinations of three factors across 400 cell types), and discovery will advance slowly using an educated trial-and-error approach.
With Mogrify still some errors are possible, but as the authors said “it provides good starting point”. They validated Mogrify by predicting transcription factors, which were previously described in direct transdifferentiation protocols and by generating 2 new cell conversions. Importantly, Mogrify was benchmarked against other, previously computational platforms, such as CellNet:
The average recovery rate of published transcription factors was 84% for Mogrify, 31% for CellNet and 51% for the method of D’Alessio et al. In six of the ten conversions shown in Figure 2, Mogrify recovered 100% of the required transcription factors; if Mogrify had been used in the original studies, the experiments could have been a success the first time. CellNet and the method of D’Alessio et al. each only recovered all the factors for one of the ten conversions.
Interesting observation was made about Yamanaka’s factors:
There have been several reports suggesting that the Yamanaka factors can initiate transdifferentiation without traversing the pluripotent state (reviewed in ref. 1). These findings have recently been challenged by Hochedlinger and Hanna. We observe that Mogrify did not predict the use of Yamanaka factors for the transdifferentiations mentioned in this report (except in conversion to iPS cells). Mogrify prediction, however, is based on the source and target regulatory networks and does not have the capacity to detect factors only transiently expressed during the reprogramming process.
I think, Mogrify is very promising tool! At this point, researchers just have to try it and try it… and report how well does it work. So, if you’re in cell reprogramming field, please try it and tell us!
Mogrify predictions will not guarantee conversion but will certainly aid in the development of transdifferentiation protocols. Other players such as noncoding RNAs, small molecules, epigenetic factors and signaling pathways provide a rich source of improvements for the future. At present, the major challenge to progress in the field of reprogramming is in increasing the number of successful cell conversions. That is what this resource makes possible, paving the way for the routine manipulation of cells, an understanding of the processes involved and the immediate translation of any breakthroughs in the clinical delivery techniques under heavy development in academia and industry.
Also read about Mogrify on the Stem Cellar blog.