Javier Caceres: RNA processing and gene regulation

The major aim of this programme is to understand the mechanisms that control gene expression at the posttranscriptional level.

Gene expression is extensively regulated at the post-transcriptional level, and this adds complexity to the human transcriptome and proteome. RNAs associate with RNA-binding proteins (RBPs) to form ribonucleoprotein (RNP) complexes, which display unique RNA-binding activity, and impact on cellular gene expression networks. We have investigated the role of RBPs in gene expression at different levels during the RNA processing cascade from splicing in the nucleus to translation in the cytoplasm. We are particularly interested in understanding how RNA processing events are regulated and how alterations to the RNA processing cascade contribute to human disease.

Major recent findings in these areas are listed below

Alternative splicing regulation

We study the mechanisms that control Alternative splicing. These include the interactions of trans-acting factors with cis-acting sequences, namely splicing enhancers and silencers, in the precursor mRNAS. We are also focusing in the kinetic control of AS, a mechanism by which the rate of RNA polymerase II (RNAPII) elongation influences alternative splicing (AS). We found a crucial role for RNAPII elongation rate in transcription and splicing of long neuronal genes involved in synapse signalling. This provides compelling evidence that transcription elongation rates have a crucial role in gene expression and the regulation of alternative splicing patterns during development. We also investigate how RNA-binding proteins (RBPs) that travel from the nucleus to the cytoplasm act to coordinate different steps in gene expression.

Nonsense-mediated decay

NMD is a translation-dependent mechanism that degrades mRNAs harboring premature termination codons (PTCs) and occurs in the cytoplasm.  We identified a novel localised NMD response at the endoplasmic reticulum (ER), which we termed ER-NMD, that provides quality control of mRNAs translated at the ER. We aim to investigate the mechanism of ER-NMD, identify the role of ER-localised and canonical NMD factors and define the biological function of ER-NMD.

miRNA biogenesis and function

We investigate the processing of precursor miRNAs to give rise to mature miRNAs that regulate gene expression. We use biochemistry and structural biology to define the interaction of trans-acting proteins with conserved sequences in precursor miRNAs We also study the contribution of genetic variation to the regulation of miRNA biogenesis. We have found that primary sequence determinants and RNA structure are key regulators of miRNA biogenesis.