Alternative Splicing in Human Pathologies Laboratory

Alternative Splicing in Human Pathologies Laboratory

Our laboratory is pioneering how alternative gene products drive human diseases and act as novel targets for therapy.

Accessing the information embedded in our DNA requires a critical process called RNA splicing. This process, like any protein-mediated reaction, is fallible and the resultant products are a diverse group of alternatively spliced RNA molecules comprising the primary source for expansion of the functional proteome. However, many of these RNA transcripts do not code for proteins, so-called non-coding RNAs, and are emerging as the most abundant master regulators of normal cellular processes and even disease (Chen & Conn (2017) Genome Biology 18: 133). Our laboratory focuses on a class of enigmatic non-coding RNAs, called circular RNAs (circRNAs), publishing seminal papers in this field.

CircRNAs are made via a type of alternative RNA splicing called back-splicing, where a downstream splice donor site fuses to an upstream acceptor site, creating a single-stranded, covalently closed circular RNA transcript (Figure 1). Lacking a 5’ cap or 3’ polyadenylation signal the vast majority of these circRNAs are untranslated.

We have found during cellular development, the levels of these circRNAs are regulated, and using a novel reporter construct (called circScreen), identified an RNA binding protein, called Quaking, which is critical for biogenesis of a large proportion of circRNAs during Epithelial-Mesenchymal Transition (EMT) (Conn et al. (2015) Cell 160: 1125-1134). Also, manipulating these circRNAs can cause cellular effects, including an impact on the alternative splicing of its cognate mRNA (Conn et al. (2017) Nature Plants 3: 17053).

In ongoing work we are examining aspects of circRNA function through profiling their interacting partners. We are utilising a number of human cancer tissue samples, relevant mouse models and in vitro stem cell culture work to assess functions of circRNAs in important biological processes and diseases.

Current research projects

  • Formation and function of circRNAs in EMT
  • The Molecular Interactome and Functions of Circular RNAs

Selected recent publications

  1. Chen JA, Conn SJ (2017) Canonical mRNA is the exception, rather than the rule. Genome Biology18: 133

Impact Factor = 11.3

  1. Conn VM, Hugouvieux V, Nayak A, Conos S, Capovilla G, Cildir G, Jourdain A, Tergaonkar V, Schmid M, Zubieta C, Conn SJ (2017) A CircRNA from SEPALLATA3 Regulates Splicing of its Cognate mRNA Through R-loop Formation. Nature Plants 3: 17053.

Impact Factor = 10.3              Citations 3

a.      Focus of News & Views article: Ariel F, Crespi M (2017) Alternative Splicing: The Lord of The Rings. Nature Plants3: 17065

b.      The first evidence of circRNAs binding to DNA, impacting alternative splicing of the cognate mRNA and driving a specific floral phenotype.

  1. Hocking B*, Conn SJ*, Manohar M, Xu B, Athman A, Stancombe MA, Webb AR, Hirschi KD, Gilliham M (2017) Heterodimerization of Arabidopsis calcium/proton exchangers contributes to regulation of guard cell dynamics and plant defense responses. Journal of Experimental Botany. Published online.

Impact Factor = 5.5

  1. Conn SJ, Pillman KA, Toubia J, Conn VM, Salmanidis M, Phillips CA, Roslan S, Schreiber AW, Gregory PA, Goodall GJ (2015) The RNA binding protein Quaking regulates formation of circRNAs. Cell 160: 1125-1134

Impact Factor = 32.2              Citations 186

a.      Ranked #1 of 1,921 Biochemistry, Genetics and Molecular Biology journals

  1. Garnett T, Plett D, Conn V, Conn S, Rabie H, Rafalksi A, Dhugga K, Tester M, Kaiser B (2015) Variation for N Uptake System in Maize: Genotypic Response to N Supply. Frontiers in Plant Science 6: 00936

Impact Factor = 4.0                Citations 1

  1. Athman A, Tanz SK, Conn VM, Jordans C, Mayo GM, Ng WW, Burton RA, Conn SJ, Gilliham M. (2014) A fast and simple in situ PCR method for localising gene expression in plant tissue. Plant Methods 10: 29

Impact Factor = 3.1                Citations 14

  1. Puranik S, Acajjaoui S, Conn S, Costa L, Conn V, Marcellin R, Melzer R, Brown E, Hart D, Theissen G, Parcy F, Dumas R, Nanao M, Zubieta C (2014) Structural basis for the oligomerization of the MADS domain transcription factor SEPALLATA3 in Arabidopsis. The Plant Cell 26: 3603-3615

Impact Factor = 9.3                Citations 23

a.      Ranked #1 of 382 Plant Science journals

 

  1. Xiol J, Spinelli P, Laussmann MA, Homolka D, Yang Z, Cora E, Couté Y, Conn S, Kadlec J, Sachidanandam R, Kaksonen M, Cusack S, Ephrussi A, Pillai RS. (2014) RNA Clamping by Vasa assembles a piRNA amplifier complex on transposon transcripts. Cell 157: 1698-1711.

Impact Factor = 32.2              Citations 82

a.      Ranked #1 of 1,921 Biochemistry, Genetics and Molecular Biology journals

  1. Conn SJ, Pillman KA, Goodall GJ (2014) Identification of nuclear RNA-binding proteins as critical factors in circular RNA (circRNA) biogenesis. FEBS J 281: 33-34

Impact Factor = 4.2

  1. Conn SJ, Hocking B, Dayod M, Xu B, Athman A, Henderson S, Auckett L, Conn V, Shearer M, Fuentes S, Tyerman S, Gilliham M (2013) Optimising hydroponic growth systems for nutritional and physiological analysis of Arabidopsis thaliana and other plants.Plant Methods 9: 4.

Impact Factor = 4.0                Citations 67

a.      Ranked #1 of 1,921 Biochemistry, Genetics and Molecular Biology journals

b.      Highly accessed (>25,000 downloads)

  1. Garnett T, Conn V, Plett D, Conn S, Zhangellini J,Mackenzie N, Enju A, Francis K, Holtham L, Roessner U, Boughton B, Bacic A, Shirley N, Rafalski A, Dhugga K, Tester M, Kaiser B (2013) The response of the maize nitrate transport system to nitrogen demand and supply across the lifecycle. New Phytologist 198: 82-94.

Impact Factor = 7.7                Citations 36

a.      Ranked #6 of 382 Plant Science journals

  1. Hermans C#, Conn SJ#, Chen J, Xiao Q, Verbruggen N (2013) An update on magnesium homeostasis mechanisms in plants, Metallomics 5: 1170-1183.

Impact Factor = 3.6                Citations 22

a.      Cover image, #joint first author

  1. Munns RJ, JamesRA, XuB, Athman A, ConnSJ, JordansC, ByrtCS, HareRA, TyermanSD, TesterM, PlettD, Gilliham M (2012) Wheat grain yield on saline soils is improved by an ancestral Na+ transporter gene. Nature Biotechnology30: 360-4.

Impact Factor = 41.5              Citations 279

a.      Ranked #1 of 260 Biotechnology journals

b.      Faculty of 1000 “recommended” paper (F1000.com/714247954)

  1. Conn SJ Berninger P, Broadley, MR, Gilliham M (2012) Exploiting natural variation to uncover candidate genes that control element accumulation in Arabidopsis thaliana. New Phytologist193: 859-66

Impact Factor = 7.7                Citations 27

a.      Ranked #6 of 382 Plant Science journals

b.      Tansley Award Silver Medal for Plant Science Excellence

c.       Editorial focus, Dolan L (2012) The New Phytologist Tansley Medal 2011,New Phytologist193: 821-2.