Dr. Caceres is a Principal Investigator at the MRC Human Genetics Unit (MRC HGU, Edinburgh) and a Professor at the School of Molecular & Clinical Medicine, University of Edinburgh. He holds a Personal Chair in RNA and Gene Expression. He studied for a B.Sc. and a Ph.D. in Molecular Biology both at the University of Buenos Aires in Argentina. In 1989, he moved to the USA to carry out postdoctoral research in the laboratory of Jim Dahlberg (University of Wisconsin-Madison), where he studied transcriptional control of small nuclear RNA genes. In 1991, he joined Adrian Krainer’s laboratory at Cold Spring Harbor, where he worked on alternative splicing regulation. He joined the MRC Human Genetics Unit in 1997. His laboratory is interested on the regulation of gene expression. Their focus is on the role of RNA-binding proteins (RNABPs) in gene expression and how alterations to RNA processing mechanisms can contribute to human disease. He serves in numerous International reviewing panels and Editorial Boards. He was elected as a member of the European Molecular Biology Organization (EMBO) in 2008 and as a fellow of the Royal Society of Edinburgh in 2011.

My laboratory is interested in the study of gene expression with a particular focus on RNA biology

The flow of genetic information from DNA to RNA to protein involves complex mechanisms of regulation, most of which act downstream of the process of transcription, which produces RNA molecules from a DNA template. Pre-mRNA splicing is the process by which non-coding intervening sequences, termed introns, are excised from precursor RNAs and the precise joining of coding sequences of exons act to form the mature messenger RNA that is exported from the nucleus for translation. Although most RNA molecules are processed in a constitutive fashion, i.e. all mRNA molecules encode the same protein; a further level of complexity is added by alternative splicing, where a series of different mRNA molecules can be produced by the differential use of splice sites within the pre-mRNA. Thus, alternative splicing enables a single gene to increase its coding capacity, allowing the synthesis of several structurally and functionally distinct protein isoforms. A single alternative splicing decision can drastically influence gene expression, affecting cellular processes as diverse as signal transduction, transcriptional regulation, cellular transformation and cell death. We are also focusing on surveillance mechanisms that eliminate mRNAs harbouring premature termination codons since accumulation of those would be deleterious for the cell. Finally, we study the mechanism by which short non-coding RNAs (termed microRNAs) regulate the expression of cellular mRNAs. Our research programme is at the basic end of the spectrum and we expect to contribute a greater understanding on how proteins that bind to RNA direct the posttranscriptional regulation of gene expression. This research will illustrate how alterations in RNA binding proteins-mediated gene regulation can contribute to human disease.

There is an extensive coupling among different steps in eukaryotic gene expression, as shown by the intimate connection between transcription and RNA processing.  Importantly, gene expression is extensively regulated at the post-transcriptional level. The fundamental steps of eukaryotic RNA processing have been characterised in great detail, but knowledge of how the disruption of these processes contributes to human disease has only recently begun to emerge. RNAs associate with RNA-binding proteins (RNABPs) to form ribonucleoprotein (RNP) complexes in cells. There is a great variety of RNABPs, each with unique RNA-binding activity giving rise to a unique RNP for each RNA and affecting processes as diverse as transcription, pre-mRNA splicing, miRNA biogenesis and function and mRNA translation. Our research programme aims to address the role of RNA-binding proteins in gene expression at different levels during the RNA processing cascade from splicing in the nucleus to translation in the cytoplasm.

The sequencing of several mammalian genomes highlighted the importance of Alternative Splicing (AS) as a centralmechanism that allows the generation of a large proteomic complexity from a limited number of genes. It has been recently estimated that transcriptsfrom 95% of multi-exon genes undergo alternative splicing, affecting many different cellular processes and having a central role in differentiation, development, and disease. Our laboratory studies the regulation of alternative splicing in mammalian cells. We are also focusing on the role of microRNAs (miRNAs) that are small non-coding RNA gene products that negatively regulate the expression of complementary messenger RNAs. We aim to understand how miRNAs are post-transcriptionally regulated and to identify trans-acting factors that regulate their production. We are also investigating how signalling pathways control the post-transcriptional regulation of miRNA biogenesis. We are also interested in surveillance mechanisms, such at the nonsense-mediated mRNA decay (NMD) pathway that acts to degrade mRNAs harbouring premature termination codons (PTCs).

In summary, the major aim of this programme is to study the mechanisms for the post-transcriptional regulation of gene expression in health and disease. We are particularly interested in understanding how RNA processing events are regulated and how alterations to the RNA processing cascade contribute to human disease.

- Ian Adams (MRC Human Genetics Unit)

- David Fitzpatrick (MRC Human Genetics Unit)

- Elizabeth Patton (MRC Human Genetics Unit)

- Gracjan Michlewski (University of Edinburgh)

External collaborators

- Eduardo Eyras (Universitat Pompeu Fabra, Barcelona, Spain)

-  Jose Luis Garcia-Perez (Pfizer-University of Granada-Andalusian Governent Center For Genomics and Oncological Research

- Alberto Kornblihtt (University of Buenos Aires, Argentina)

-  Adrian Krainer (Cold Spring Harbor Laboratory, USA)

- Oscar Llorca (Centro de Investigaciones Biológicas (CIB), Madrid, Spain)

- Nick Proudfoot (University of Oxford, UK)

- Michael Sattler (Technical University, Munich, Germany)