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Tudor Fulga

Associate Professor of Genome Biology


Every cell within our body carries the same genetic information, yet following iterative developmental transitions hundreds of morphologically and functionally distinct cell types are generated. At the foundation of this fascinating cellular diversification, lies a milieu of finely orchestrated and sophisticated regulatory programmes, which act to turn on or off thousands of genes (~20,000 in humans) with minute spatial and temporal precision. Errors in these programmes can give rise to developmental defects and many human diseases including cancer. For many years, it was thought that RNAs only function as structural scaffolds and messengers transferring genetic information from DNA to proteins. This view was drastically changed following the seminal discovery of RNA interference and endogenous non-coding regulatory RNAs. This discovery revolutionized our view on the regulation of gene expression networks, setting an important milestone in molecular, developmental and disease biology. While tremendous progress has been made in understanding the complexity and importance of non-coding RNAs, it is clear that the most significant insights still lie ahead. Our research programme aims to decipher the role of non-coding regulatory RNAs in development and human diseases, and engineer innovative RNA-based synthetic devices for diagnostic and therapeutic applications. The projects pursued in the lab can be divided in three interconnected directions:


During the last decade, microRNAs (miRNAs) have emerged as critical regulators of gene expression programs in development and disease. miRNAs are ~22 nucleotide endogenous non-coding RNAs that bind to specific miRNA response elements (MREs) in target RNAs, and post-transcriptionally silence gene expression primarily via RNA decay or translational inhibition. Hundreds of miRNAs have been identified in various species, and it is estimated that they collectively have the potential to target more than half of all mRNAs in vertebrates. Despite rapid progress in understanding the molecular mechanisms underlying miRNA biogenesis and mechanisms of action, the biological functions of most miRNAs remain elusive at an organismal level. Our goal is to elucidate the function of miRNAs in animal development, understand their contribution to certain human pathological conditions, and uncover the molecular mechanisms governing miRNA target recognition and silencing. These studies take advantage of a multi-disciplinary experimental platform combining versatile transgenic technologies, RNA biochemistry, molecular biology, bioinformatics, advanced imaging, high-throughput genomic tools, and cutting-edge genome engineering technologies.


Cellular reprogramming using synthetic gene networks offers much promise as a novel therapeutic tool. Underpinning this idea is the need to generate versatile synthetic devices capable of precise assessment of cellular state and regulation of therapeutic actuation. A central theme in our group is to repurpose the functionality contained within RNA molecules to develop molecular devices capable of rewiring cellular behavior. Attaining this goal requires a rational design process and in vitro evolution strategies, to assemble RNA-based logic gates into biological computers activated by endogenous triggers. miRNA expression profiles can serve as unique signatures differentiating cells based on type as well as physiological state (i.e. disease state), and could form an ideal input for such systems. The resulting synthetic devices have potential for widespread applications ranging from basic tools for miRNA research, to components in targeted diagnostic and therapeutic strategies. This work falls under the broad spectrum of synthetic biology, encompassing fields as diverse as biomedical sciences, engineering and computer sciences.


The recent advent of sophisticated genome engineering technologies including transcription activator-like effector nucleases (TALENs) and programmable RNA-guided endonucleases (CRISPR/Cas9), revolutionized biomedical research and created an unprecedented exploratory landscape for basic research, disease studies and therapeutic applications. We have recently developed a powerful experimental platform, which takes advantage of genome engineering to enable rapid interrogation of physiologically relevant MREs and assess their activity in intact biological systems. Using this approach we showed that the activity of MREs is influenced by miRNA : target stoichiometry, and loss of MREs can result in dramatic phenotypes during development. We are currently expanding this experimental framework to multiplex high-throughput analysis of MRE activity in cultured cells. These studies promise to engender unprecedented insight into the principles and rules governing miRNA target selection in the context of a regulatory cellular network. In parallel, we continue to develop new dimensions of genome engineering technologies aimed to advance their in vivo versatility.

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Selected Publications


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