Cellular replacement therapies for treating degenerative diseases such as Alzheimers will require the generation of lost tissues by reprogramming cell types. While one strategy is to de-differentiate somatic cells into induced pluripotent stem cells with subsequent re-differentiation, an alternative strategy is to directly convert cells to the target cell type by using specific Transcription Factors (TFs). The latter strategy utilizes TFs that can induce specific cell fates; however, their ability to reprogram cell identities upon mis-expression is very limited. We are elucidating refractory mechanisms of direct cell fate conversion using C. elegans as a model organism. Using RNAi screens we recently identified LIN-53 (homolog of Rbbp4/7) as an inhibitor of reprogramming mitotic germ cells directly into specific neurons and muscle-like cells. At least six different chromatin regulatory complexes such as NURF/NuRD remodelling and histone modifying complexes share LIN-53. However, the molecular function of LIN-53 in different tissues and its exact role in regulating reprogramming remains elusive. Furthermore, forward genetics screens identified a ubiquitin specific protease (USP) to be involved in regulating direct reprogramming of hypodermal (skin) cells in worms. Nothing is known about this USP, only that its homolog is a direct target of the ectodermal master regulator p63 in human skin cells. Using 4D time-lapse imaging and tissue-specific biochemistry (ChIP-seq, SILAC) we aim to determine the spatio-temporal expression pattern of both factors in vivo and investigate their molecular function in controlling cell fate reprogramming. We will elucidate the regulatory network of these reprogramming factors by complementing our examinations with genetic analysis. Our findings might have broad implications for understanding mechanisms that restrict direct cell fate reprogramming and for generating specific tissues from different cellular contexts.
Start Date: 2013-04-01 End Date: 2017-03-31 EU Contribution: 100 000 Euro Total Costs: 100 000 Euro Programme Acronym: FP7-People Subprogramme Area: FP7-PEOPLE-2011-CIG Funding Scheme: Support for training and career development of researcher (Life Sciences) Administrative Contact Person: Ioannis LEGOURAS (Dr) CORDIS-Link