AUG 21, 2013 04:00 PM PDT

The hidden layer of RNA regulation in human development

  • Executive Director, Garvan Institute of Medical Research, Conjoint Professor in the St Vincent's Hospital Clinical School and the Faculty of Medicine, at the University of New South Wale
      John joined the Garvan Institute as the Executive Director in January 2012. He has made a significant contribution to the understanding of genetics and genomics through his farsighted theories on 'junk' DNA, the large non-coding sections of the human genome that do not code for proteins. Most recently John was the Professor of Molecular Biology and NHMRC Australia Fellow at the Institute for Molecular Bioscience, University of Queensland. John was educated at St Patrick's College Strathfield, the University of Sydney and Monash University, where he obtained his PhD. He has subsequently worked at Baylor College of Medicine in Houston, the CSIRO Division of Molecular Biology in Sydney, and the University of Queensland, where he was based from 1988-2011. He has also spent research periods at the Universities of Cambridge, Oxford, Cologne and Strasbourg. He was Foundation Director of the Australian Genome Research Facility and the Institute for Molecular Bioscience.


    High throughput transcriptomic analyses have shown that most of the human genome is dynamically transcribed to produce an extraordinary range of overlapping and interlacing intronic, intergenic and antisense RNAs, many of which are alternatively spliced, to produce a previously hidden universe of long and short regulatory RNAs. These RNAs fulfill various functions in gene expression, with miRNAs and related species being best (although not well) understood. The functions of the long noncoding RNAs (lncRNAs), which range from hundreds to hundreds of thousands of bases in length, are varied and include central roles in the formation of various differentiation-specific subnuclear organelles. However, recent evidence suggests that the major function of lncRNAs is to guide chromatin-modifying complexes to their sites of action, to specify the architectural trajectories of development and differentiation. In addition, it appears that these RNAs are subject to context-dependent editing, particularly in the brain, which appears to be, along with transposon mobility, the molecular basis of physiological and cognitive plasticity. The transcriptome is in fact far more complex than the genome, which is best viewed as a zip file that is unpacked in highly cell-specific patterns during development. Focused RNA sequencing (using oligonucleotide capture to target specific loci, similar to exome sequencing) reveals thousands of previously unknown exons and spliced isoforms of oncogenes and tumor suppressors, as well as a rich landscape of lncRNAs expressed from genomic regions, including GWAS regions associated with complex diseases, that superficially appear to be transcriptionally bare by conventional deep sequencing. Not surprisingly, it is also emerging that variations in the sequence or expression of these RNAs not only underpin phenotypic differences between individuals and species, but also play significant roles in the etiology of complex diseases, including as cancer and neurological diseases.

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