Clark laboratory: Transcriptomics and Neurogenetics

Researcher

Research Overview

We work at the intersection of genomics and neuroscience, utilising a number of transcriptomic (RNA-Seq, Nanopore long-read sequencing, targeted RNA sequencing and single cell sequencing) and functional genomic approaches to investigate gene expression and function in the human brain and in neuropsychiatric disorders. Our laboratory has two main areas of investigation.

1. Risk genes for neuropsychiatric disorders

  • Many regions in our DNA are known to confer risk to disease, including neuropsychiatric disorders such as schizophrenia and bipolar disorder, but the genes responsible and how they confer risk are often unknown. We are interested in identifying these genes, both protein coding and noncoding (i.e.: long noncoding RNAs) and how their expression can change to cause disease risk. We utilise both mortem human brain and neurons derived from induced pluripotent stem cells (iPSCs) to help answer these questions.

2. Novel applications of Nanopore sequencing

  • A second research area is to develop and utilise novel sequencing methods. We have worked in the past to help develop targeted RNA sequencing to allow highly sensitive detection and quantification of genes of interest. More recently we have focused on utilising Nanopore sequencing, a technology that can sequence both DNA and native RNA. We are applying Nanopore sequencing to many research questions as well as developing novel applications for this technology.

In addition, we have interests in multiple aspects of RNA biology including noncoding RNAs and RNA post-transcriptional regulation.

Collaborators

Paul Harrison, University of Oxford, UK
Elizabeth Tunbridge, University of Oxford, UK
Wilfried Haerty, Earlham Institute, UK
Zameel Cader, University of Oxford, UK
Adam Handel, University of Oxford, UK
Rory Bowden, Oxford Genomics Centre, UK
Adrien Leger, EMBL-EBI, UK
Daniel Winberger, Lieber Institute for Brain Development, USA

Funding

NHMRC CJ Martin Biomedical Fellowship (2014-2020)
MRC Research Grant (2017-2019): Brain-enriched voltage-gated calcium channel isoforms: novel, genetically informed, therapeutic targets for psychiatric disorders
Wellcome Trust Seed Award (2016-2017): Capture NanoporeSeq: A novel technique for targeted full-length transcript sequencing and gene expression analysis
EMBO Long Term Fellowship (2014-2016)

Research Publications

  1. Bartonicek N, Clark MB, Quek XC, Torpy JR, Pritchard AL, Maag JLV, Gloss BS, Crawford J, Taft RJ, Hayward NK, Montgomery GW, Mattick JS, Mercer TR, Dinger ME. (2017) Intergenic disease-associated regions are abundant in novel transcripts. Genome Biol 18(1): 241.
  2. Bussotti G, Leonardi T, Clark MB, Mercer TR, Crawford J, Malquori L, Notredame C, Dinger ME, Mattick JS, Enright AJ. (2016) Improved definition of the mouse transcriptome via targeted RNA sequencing. Genome Res. 26(5):705-16.
  3. Clark MB*, Mercer TR*, Bussotti G, Leonardi T, Haynes KR, Crawford J, Brunck ME, Lê Cao K, Thomas GP, Chen WY, Taft RJ, Nielsen LK, Enright AJ, Mattick JS, Dinger ME (2015). Quantitative gene profiling of long-noncoding RNAs with targeted RNA sequencing. Nature Methods. 12(4):339- 342 (* Joint first authors).
  4. Mercer TR*, Clark MB*, Andersen SB, Brunck ME, Haerty W, Crawford J, Taft RJ, Nielsen LK, Dinger ME, Mattick JS (2015). Genome-wide discovery of human splicing branchpoints. Genome Res. 25(2): 290-303 (* Joint first authors).
  5. Mercer TR*, Clark MB*, Crawford J*, Brunck ME, Gerhardt DJ, Taft RJ, Nielsen LK, Dinger ME, Mattick JS. (2014). Targeted sequencing for gene discovery and quantification using RNA CaptureSeq. Nat Protoc. 9(5):989-1009. (* Joint first authors)
  6. Mercer TR, Edwards SL, Clark MB, Neph SJ, Wang H, Stergachis AB, John S, Sandstrom R, Li G, Sandhu KS, Ruan Y, Nielsen L, Mattick JS, Stamatoyannopoulos JA. (2013). DNaseI- hypersensitive exons co-localize with promoters and distal regulatory elements. Nat Genet. 45(8): 852-859.
  7. Clark MB, Johnston RL, Inostroza-Ponta M, Fox AH, Fortini E, Moscato P, Dinger ME, Mattick JS. (2012). Genome-wide analysis of long noncoding RNA stability. Genome Res. 22(5): 885-898.
  8. Clark MB, Amaral PP, Schlesinger FJ, Dinger ME, Taft RJ, Rinn JL, Ponting CP, Stadler PF, Morris KJ, Morillon A, Rozowsky JS, Gerstein M, Wahlestedt C, Hayashizaki Y, Carninci P, Gingeras TR, Mattick JS. (2011). The reality of pervasive transcription. PLoS Biol 9(7): e1000625.
  9. Clark MB, Mattick JS. (2011). Long noncoding RNAs in cell biology. Semin Cell Dev Biol. 22(4): 366- 376.
  10. Amaral PP*, Clark MB*, Gascoigne DK*, Dinger ME, Mattick JS. (2011). lncRNAdb: a reference database for long noncoding RNAs. Nucleic Acids Res 39: D146-151. (* Joint first authors).

In preprint:

Clark MB*, Wrzesinski T*, García-Bea A, Kleinman JE, Hyde T, Weinberger DR, Haerty W, Tunbridge EM. Long-read sequencing reveals the splicing profile of the calcium channel gene CACNA1C in human brain. Biorxiv 5th Feb 2018 doi:10.1101/260562 (* Joint first authors).

Research Projects



Faculty Research Themes

Neuroscience

School Research Themes

Biomedical Neuroscience, Stem Cells, Molecular Mechanisms of Disease



Key Contact

For further information about this research, please contact Head of Laboratory Dr Mike Clark

Department / Centre

Anatomy and Neuroscience

Unit / Centre

Clark laboratory


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