The physiological role of microRNAs in determining call fate

Recent months have seen rapid advances in the field of transdifferentiation, specifically in the conversion of fibroblasts to neurons. Most surprising is the observation that the ability to drive these transitions is not limited to transcription factors, but that they can be promoted bymicroRNAs aswell. Indeed, in one case, microRNAs alone induced the transdifferentiation of fibroblasts to neuron-like cells, albeit at a low efficiency. Here, we review this rapidly advancing field, discuss possiblemechanisms underlyingmicroRNAinduced transdifferentiation and the potential for microRNAs to drive such transitions to any cell type of interest in vitro and in vivo. Introduction The holy grail of regenerative medicine is to replace the damaged or lost cells that occur as we age, suffer disease, or are exposed to environmental insults. In theory regeneration could be achieved using the processes of dedifferentiation (reprogramming of a differentiated cell to revert to a stem cell), or transdifferentiation (reprogramming one type of differentiated cell to become another sort of differentiated cell). Recent advances have shown that these phenomena can be induced in adult mammalian cells by modulating the expression of particular genes. In 1987, Weintraub and colleagues made the pioneering discovery that the addition of a single transcription factor could convert a fibroblast to a muscle cell [1]. In recent years, the number of examples of transcription factorinduced transdifferentiation is growing at a remarkable rate. In 2004, Graf and colleagues induced mouse B-lymphocytes into macrophages [2]. In 2008, Melton and colleagues described the transdifferentiation ofmouse pancreatic acinar cells to beta-islet cells [3]. Two years later, Wernig and colleagues induced the conversion of mouse fibroblasts to neurons, showing for the first time that addition of transcription factors can induce transdifferentiation across germ layers – from cell types formed in the mesoderm to those formed in the ectoderm [4]. These efforts were originally performed using mouse cells. A recent litany of papers has taken it a step further directing the conversion of human fibroblasts to neurons as well as the differentiation to specific neuronal subtypes [5-11]. MicroRNAs can change cell fate While most transdifferentiation experiments have used cocktails of transcription factors ranging from three to as many as eleven, two recent studies have included microRNAs. microRNAs are short non-coding RNAs approximately twenty-one nucleotides in length that bind to complementary pieces of mRNA after transcription and inhibit their translation. Like transcription factors, they can regulate hundreds of targets simultaneously. Also like transcription factors, they recognize short motifs (7-8 nucleotides) in their targets [12]. For microRNAs, these motifs are predominantly in the 3’UTRs (untranslated regions) and occasionally the coding region of mRNAs. In contrast, transcription factors bind DNA motifs within promoter and enhancer regions of the genome’s DNA. Transcription factors havebeenaccepted aspotentialmaster regulators of cell fate ever since Weintraub’s seminal work. In contrast,microRNAs have rarely been thought of as such. Indeed, they are more typically described as stabilizers of cell fates or buffers of stochastic transcriptional noise and