RNA Systems Biology Laboratory

The RNA Systems Biology Laboratory asks how cells regulate the birth, life and death of RNA molecules using Next Generation Sequencing (NGS).

We are experiencing a major re-think in cell biology. Up until very recently, the major focus in gene-regulation was on DNA and DNA-binding proteins. However, it turns out that RNA is not just a passive intermediary between DNA and proteins; RNA also has structural and regulatory functions in addition to its coding functions. Therefore, the RNA Systems Biology Laboratory is interested in how both coding and non-coding RNA is expressed and regulated in cells, and how the fine-tuning of this expression, which differentiates health from disease, is maintained.

NGS provides a holistic, systems level view of the RNA expression profile in cells, and since disease often leaves signature fingerprints of deregulation on such profiles, NGS can be a powerful diagnostic for various disease states including for cancer. The RNA Biology laboratory uses custom RNA-seq technologies in a diverse set of model organism and cultured-cells to study RNA dynamics. Specifically, we are interested in the post-transcriptional regulation of RNA that determines when, where and how often, mRNA is translated to make proteins. Because we seek to understand how every RNA in our system is regulated, our experiments often have 100s of millions of data-points and thus require the input of computational biologists.

Most Recent Publications

Integration of Posttranscriptional Gene Networks into Metabolic Adaptation and Biofilm Maturation in Candida albicans.

Verma-Gaur J, Qu Y, Harrison PF, Lo TL, Quenault T, Dagley MJ, Bellousoff M, Powell DR, Beilharz TH, Traven A.

The yeast Candida albicans is a human commensal and opportunistic pathogen. Although both commensalism and pathogenesis depend on metabolic adaptation, the regulatory pathways that mediate metabolic processes in C. albicans are incompletely defined. For example, metabolic change is a major feature that distinguishes community growth of C. albicans in biofilms compared to suspension cultures, but how metabolic adaptation is functionally interfaced with the structural and gene regulatory changes that drive biofilm maturation remains to be fully understood. We show here that the RNA binding protein Puf3 regulates a posttranscriptional mRNA network in C. albicans that impacts on mitochondrial biogenesis, and provide the first functional data suggesting evolutionary rewiring of posttranscriptional gene regulation between the model yeast Saccharomyces cerevisiae and C. albicans. A proportion of the Puf3 mRNA network is differentially expressed in biofilms, and by using a mutant in the mRNA deadenylase CCR4 (the enzyme recruited to mRNAs by Puf3 to control transcript stability) we show that posttranscriptional regulation is important for mitochondrial regulation in biofilms. Inactivation of CCR4 or dis-regulation of mitochondrial activity led to altered biofilm structure and over-production of extracellular matrix material. The extracellular matrix is critical for antifungal resistance and immune evasion, and yet of all biofilm maturation pathways extracellular matrix biogenesis is the least understood. We propose a model in which the hypoxic biofilm environment is sensed by regulators such as Ccr4 to orchestrate metabolic adaptation, as well as the regulation of extracellular matrix production by impacting on the expression of matrix-related cell wall genes. Therefore metabolic changes in biofilms might be intimately linked to a key biofilm maturation mechanism that ultimately results in untreatable fungal disease.

PLoS Genet. 2015
3'UTR Tracks for upload to the Candida Genome Database
POS-1 Promotes Endo-mesoderm Development by Inhibiting the Cytoplasmic Polyadenylation of neg-1 mRNA.

Elewa A, Shirayama M, Kaymak E, Harrison PF, Powell DR, Du Z, Chute CD, Woolf H, Yi D, Ishidate T, Srinivasan J, Bao Z, Beilharz TH, Ryder SP, Mello CC.

The regulation of mRNA translation is of fundamental importance in biological mechanisms ranging from embryonic axis specification to the formation of long-term memory. POS-1 is one of several CCCH zinc-finger RNA-binding proteins that regulate cell fate specification during C. elegans embryogenesis. Paradoxically, pos-1 mutants exhibit striking defects in endo-mesoderm development but have wild-type distributions of SKN-1, a key determinant of endo-mesoderm fates. RNAi screens for pos-1 suppressors identified genes encoding the cytoplasmic poly(A)-polymerase homolog GLD-2, the Bicaudal-C homolog GLD-3, and the protein NEG-1. We show that NEG-1 localizes in anterior nuclei, where it negatively regulates endo-mesoderm fates. In posterior cells, POS-1 binds the neg-1 3' UTR to oppose GLD-2 and GLD-3 activities that promote NEG-1 expression and cytoplasmic lengthening of the neg-1 mRNA poly(A) tail. Our findings uncover an intricate series of post-transcriptional regulatory interactions that, together, achieve precise spatial expression of endo-mesoderm fates in C. elegans embryos.

2015 Developmental Cell
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