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The RNA biology and plasticity laboratory

The central hypothesis/heuristic of the Mattick Lab--which is now situated at the Garvan Institute of Medical Research in Sydney--is that the majority of the genomes of complex organisms is devoted to an RNA regulatory system, and that this was the enabling platform for the evolution and development of complex multicellular organisms.

The new RNA world

The central dogma of molecular biology confines the role of RNA to that of a messenger in the cell, conveying the genetic code required for protein synthesis from DNA in the nucleus to the translational machinery in the cytosol. The human genome contains ~25,000 such protein-coding genes, an amount that varies little throughout most animal phyla. However, the ratio of non-coding (once referred to as “junk” DNA) to protein-coding DNA increases proportionately to the developmental complexity of most organisms, suggesting that genomic “dark matter” may be involved in the evolution of multicellular complexity and in the developmental ontologies of higher eukaryotes. For example, this ratio is approximately 3:7 in the yeast S. cerevisiae (1 cell), 3:1 in the nematode worm C. elegans (~1000 cells), and 50:1 in Homo sapiens (>10 trillion cells).

Recent high-throughput sequencing analyses has revealed that at least 75% of the human genome is dynamically transcribed to RNA in some tissue at some point in time. The resulting plethora of transcribed sequences presents an analytic challenge in itself, which is compounded by higher-order structure formation, inter-molecular associations, and post-transcriptional modifications. Our laboratory is devoted to further understanding the functional mechanisms involving non-coding RNAs in complex genetic phenomena like development and cognition, through both experimental and computational analyses predicated on next generation sequencing technologies.

Evolution of complex regulatory networks in higher eukaryotes

Given the relatively stable set of protein-coding genes, it is clear that most evolutionary adaptation occurs in regulatory sequences. For example, the occurrence of DNA k-mers (i.e. DNA “words” of length k) follows a multi-modal distribution in tetrapod genomes, whereas fish and less complex metazoans present a unimodal k-mer distribution. Furthermore, the non-uniform distribution of specific k-mers suggests that regulatory networks can be discovered prima facie through computational analysis. How can developmental trajectories, cellular differentiation, and conditional gene expression be inferred from such observations?

The pervasive transcription of mammalian genomes provides a large, dynamic pool of transcripts for selection to act upon. Such regulatory sequences are fast evolving and show little conservation over long evolutionary distances, as most ncRNAs are subject to more flexible structure-function constraints than protein-coding RNAs (e.g. RNAs that function via their secondary and tertiary structures). By providing specificity to generic protein complexes, ncRNAs can act as guides to selectively target effector proteins to different loci and thereby regulate the transcription or translation of many genes. The identification, characterization and experimental validation of such interactions will provide valuable insights into the biological mechanisms underlying evolution and complex diseases. Regulatory sequences are also subject to positive selection for adaptive radiation. Transposable elements and other repeats (which compose ~50% of the human genome) are frequently present in long non-coding RNAs. Sequences from such genetic elements can be “domesticated” during evolution and contribute to ncRNA function by promoting their expression and providing functional motifs. One particular class of repeat elements, ALUs, have multiplied extensively in primates and are selectively targeted for RNA editing (adenosine deamination).

Plasticity and adaptability of genetic regulation

Both embryonic development and brain function are dependent on epigenetic processes (modifications in gene expression not involving the core DNA sequence), which are controlled by RNA signaling. Most long ncRNAs are expressed in the brain, many in exquisitely precise patterns in regions of the brain important for cognition such as the hippocampus. The brain has an extraordinarily complex RNA metabolism, where transcripts are widely altered by RNA editing.

There are two types of RNA editing, both involving base deamination: (i) Cytosine to uracil (C>U) editing carried out by ApoB editing complexes (APOBECs). C>U editing is involved in a variety of functions, including development, immunoglobulin hypervariation and defense against retrotransposons, the last of which may be involved in somatic plasticity in the brain; (ii) Adenosine to inosine (A>I) editing is predominantly found in the brain and involves 3 enzymes (ADAR1,2 and 3), although little is known of their substrate ranges and roles. All evidence strongly suggests that there is widespread activity-dependent RNA editing in neurons and that elucidating its role will represent a major step forward in our understanding of higher-order cognition and, potentially, RNA-directed non-Mendelian epigenetic inheritance.

Academic research projects

The Mattick lab currently has availabilities for prospective Honour's, Master's or PhD projects through UNSW. If you are interested in such undertakings, please send your CV, academic transcripts as well as a summary of your research interests to one of the following lab members:

Dr Eva Maria Novoa -- e.novoa[at]garvan.org.au -- Projects available

Dr Martin Smith -- m.smith[at]garvan.org.au -- 2 research projects available

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