Both epigenetic factors and microRNAs have the potential to control transcript levels of large sets of genes through transcriptional and post-transcriptional mechanisms. Faithful stem cell function is crucial for tissue maintenance and repair throughout life and requires these machineries to establish specific and dynamic transcription programs. However, how miRNAs and chromatin-factors cooperate to achieve this is poorly characterized. I previously developed genetic screening and computational approaches to determine the contribution of functional interplay among 332 chromatin-factors to epidermal differentiation. Now, I will pioneer the concept of genetic interactions between coding (chromatin-factors) and non-coding RNAs (miRNAs) using primary human epidermal stem cells as a well-characterised and clinically relevant model system. My lab will: (1) silence all individual miRNAs expressed in these cells to measure their contribution to stem cell renewal and differentiation. Innovative Bayesian statistics will then be employed to predict which miRNAs and chromatin-factors function together in functional/genetic interactions. (2) We will investigate the mechanism underlying these interactions using genomic, proteomic and cell biological approaches with particular attention to direct cooperation of nuclear miRNAs and chromatin-modifiers in transcription regulation. Together, understanding which genes in the genome cooperate, and how they do so, will not only deepen our understanding of normal biology, it will also help rationalise targeted (combination) therapies for disease, a major goal in modern clinical medicine.