
Professor Helen White-Cooper
Head of Molecular Biosciences Division
- white-cooperh@cardiff.ac.uk
- +44 (0)29 2087 5492
- W3.21, Sir Martin Evans Building, Museum Avenue, Cardiff, CF10 3AX
- Available for postgraduate supervision
Overview
Research overview
Developmental Genetics - Regulation of Gene Expression in Drosophila Spermatogenesis
Cell differentiation is driven by co-ordinated changes in the gene expression profile of the cell: some genes are switched on, others are switched off. The mature sperm is a highly specialised cell (nearly 2mm long), whose formation from a simple primary spermatocyte involves meiosis to form round spermatids, followed by complex changes in cell architecture to form the final elongated motile sperm. During spermatogenesis there is a dramatic switch in the gene expression profile of male germ-line cells: as they enter the primary spermatocyte stage they activate transcription of a large set of genes required for sperm production. We have identified a set of proteins, encoded by the meiotic arrest genes, that work together to activate this transcriptional programme, and are investigating the composition, activity and evolution of this complex. We recently discovered that another small set of genes is transcribed after meiosis, and that these late transcribed mRNAs localise to a discrete region of the cell. We are studying their transcriptional control, and the mRNA localisation mechanism. Continued production of sperm is maintained via a stem cell system, and we are characterising a transcription factor required for stem cell maintenance.
Biography
I graduated from Cambridge University with a BA in Natural Sciences (Zoology) in 1990, then went to Dundee University to carry out PhD research on the regulation of cell division in fruit flies. In 1995 I went to Stanford University in California for a period of post-doctoral research, concentrating on the role of specific genes co-ordination of various cellular events during sperm production in flies. In 1998 I moved to Oxford to set up my own lab, initially as a departmental lecturer, and in 2001 earned Royal Society University Research Fellowship. I continued to focus on spermatogenesis in Drosophila, specifically looking at regulation and function of testis specific genes. In April 2008 I moved to Cardiff University, to take up a position as a Senior Lecturer, continuing with the fly testis research. I was promoted to Reader in 2011 and to Professor in 2014.
Publications
2020
- van der Graaf, K.et al. 2020. Roles for RNA export factor, Nxt1, in ensuring muscle integrity and normal RNA expression in Drosophila.. G3 (10.1093/g3journal/jkaa046)
2018
- Laktionov, P. P.et al. 2018. Genome-wide analysis of gene regulation mechanisms during Drosophila spermatogenesis. Epigenetics and Chromatin 11, article number: 14. (10.1186/s13072-018-0183-3)
2016
- Sutton, E.et al. 2016. Identification of genes for engineering the male germline of Aedes aegypti and Ceratitis capitata. BMC Genomics 17, article number: 948. (10.1186/s12864-016-3280-3)
2014
- Lowe, N.et al. 2014. Analysis of the expression patterns, subcellular localisations and interaction partners of Drosophila proteins using a pigP protein trap library. Development 141(20), pp. 3994-4005. (10.1242/dev.111054)
- Lakitionov, P. P.et al. 2014. Transcription factor Comr acts as a direct activator in the genetic program controlling spermatogenesis in D. melanogaster. Molecular Biology 48(1), pp. 130-140. (10.1134/S0026893314010087)
2013
- Caporilli, S.et al. 2013. The RNA export factor, Nxt1, is required for tissue specific transcriptional regulation. PLOS Genetics 9(6), article number: e1003526. (10.1371/journal.pgen.1003526)
- White-Cooper, H. and Caporilli, S. 2013. Transcriptional and post-transcriptional regulation of Drosophila Germline stem cells and their differentiating progeny. In: Hime, G. and Abud, H. eds. Transcriptional and Translational Regulation of Stem Cells., Vol. 1. Advances in Experimental Medicine and Biology Vol. 786. Dordrecht: Springer, pp. 47-61., (10.1007/978-94-007-6621-1_4)
2012
- White-Cooper, H. 2012. Tissue, cell type and stage-specific ectopic gene expression and RNAi induction in the Drosophila testis. Spermatogenesis 2(1), pp. 11-22. (10.4161/spmg.19088)
2011
- Doggett, K.et al. 2011. Wake-up-call, a lin-52 paralogue, and always early, a lin-9 homologue physically interact, but have opposing functions in regulating testis-specific gene expression. Developmental Biology 355(2), pp. 381-393. (10.1016/j.ydbio.2011.04.030)
- White-Cooper, H. and Davidson, I. 2011. Unique aspects of transcription regulation in male germ cells. Cold Spring Harbor Perspectives in Biology 3(7), article number: a002626. (10.1101/cshperspect.a002626)
2010
- Miles, A.et al. 2010. OpenFlyData: An exemplar data web integrating gene expression data on the fruit fly Drosophila melanogaster. Journal of Biomedical Informatics 43(5), pp. 752-761. (10.1016/j.jbi.2010.04.004)
- White-Cooper, H. and Bausek, N. 2010. Evolution and spermatogenesis. Philosophical Transactions of the Royal Society of London Series B Biological Sciences 365(1546), pp. 1465-1480. (10.1098/rstb.2009.0323)
- Fu, G.et al. 2010. Female-specific flightless phenotype for mosquito control. Proceedings of the National Academy of Sciences of the United States of America 107(10), pp. 4550-4554. (10.1073/pnas.1000251107)
- Zhao, J.et al. 2010. FlyTED: The Drosophila testis gene expression database. Nucleic Acids Research 38(S1), pp. D710-D715. (10.1093/nar/gkp1006)
- White-Cooper, H. 2010. Molecular mechanisms of gene regulation during Drosophila spermatogenesis. Reproduction 139(1), pp. 11-21. (10.1530/REP-09-0083)
2009
- Morris, C., Benson, E. and White-Cooper, H. 2009. Determination of gene expression patterns using in situ hybridization to Drosophila testes. Nature Protocols 4(12), pp. 1807-1819. (10.1038/nprot.2009.192)
- Sato, A.et al. 2009. Degenerate evolution of the hedgehog gene in a hemichordate lineage. Proceedings of the National Academy of Sciences of the United States of America 106(18), pp. 7491-7494. (10.1073/pnas.0810430106)
- White-Cooper, H. 2009. Studying how flies make sperm-Investigating gene function in Drosophila testes. Molecular and Cellular Endocrinology 306(1-2), pp. 66-74. (10.1016/j.mce.2008.11.026)
2008
- Barreau, C.et al. 2008. Post-meiotic transcription in Drosophila spermatogenesis. Development 135(11), pp. 1897-1902. (10.1242/dev.021949)
- Barreau, C., Benson, E. and White-Cooper, H. 2008. Comet and cup genes in Drosophila spermatogenesis: the first demonstration of post-meiotic transcription. Biochemical Society Transactions 36(3), pp. 540-542. (10.1042/BST0360540)
- Kirchner, J.et al. 2008. Drosophila Uri, a PP1alpha binding protein, is essential for viability, maintenance of DNA integrity and normal transcriptional activity. BMC Molecular Biology 9: 36 (10.1186/1471-2199-9-36)
- Townley, H. E., Parker, A. R. and White-Cooper, H. 2008. Exploitation of diatom frustules for nanotechnology: tethering active biomolecules. Advanced Functional Materials 18(2), pp. 369-374. (10.1002/adfm.200700609)
- Nair-Roberts, R. G.et al. 2008. Stereological estimates of dopaminergic, GABAergic and glutamatergic neurons in the ventral tegmental area, substantia nigra and retrorubral field in the rat. Neuroscience 152(4), pp. 1024-31. (10.1016/j.neuroscience.2008.01.046)
2007
- Jiang, J.et al. 2007. Tombola, a tesmin/TSO1 family protein, regulates transcriptional activation in the Drosophila male germline and physically interacts with Always early. Development 134, pp. 1549-1559. (10.1242/dev.000521)
2004
- L, P.et al. 2004. Regulation of transcription of meiotic cell cycle and terminal differentiation genes by the testis-specific Zn finger protein matotopetli. Development 131, pp. 1691-1702. (10.1242/dev.01032)
- Korenjak, M.et al. 2004. Native E2F/RBF complexes contain Myb-interacting proteins and repress transcription of developmentally controlled E2F target genes. Cell 19(2), pp. 181-193. (10.1016/j.cell.2004.09.034)
2003
- Jiang, J. and White-Cooper, H. 2003. Transcriptional activation in Drosophila spermatogenesis involves the mutually dependent function of aly and a novel meiotic arrest gene cookie monster. Development 130(3), pp. 563-573. (10.1242/dev.00246)
Regulation of Gene Expression in Drosophila Spermatogenesis
Cell differentiation is driven by co-ordinated changes in the gene expression profile of the cell: some genes are switched on, others are switched off. One of the most astonishing developmentally regulated changes in cell morphology occurs in spermatogenesis. The mature sperm is a highly specialised cell, whose formation from a simple primary spermatocyte involves an unusual cell division (meiosis) to form a round spermatid, followed by complex changes in the cell architecture to form the final elongated motile sperm. These differentiation events require many gene products used at no other time in development. Underlying this there is a dramatic switch in the gene expression profile of male germ-line cells: as they enter the primary spermatocyte stage they activate transcription of a large set of genes required for sperm production. We have recently discovered that another small set of genes is transcribed after meiosis, in elongating spermatids, and are investigating their role in sperm function.
The meiotic arrest loci
The meiotic arrest class of Drosophila genes regulate transcription in spermatogenesis; specifically they are required for activation of expression of numerous genes required for spermatid differentiation. A series of micro-array experiments revealed that approximately half of all Drosophila protein coding genes are expressed in testes, and that 15-20% of these are regulated by our genes, ie, the meiotic arrest genes control transcription of up to 10% of all Drosophila protein coding genes. We cloned and characterised five of these meiotic arrest genes (aly, comr, achi/vis, topi and tomb). aly and comr have unknown functions, topi, tomb and achi/vis encode DNA binding proteins. In normal primary spermatocytes all the meiotic arrest proteins are chromatin associated, consistent with their role in gene-expression regulation. Their localisation in different mutant backgrounds varies: e.g. aly function is required for the nuclear localisation of Comr, and vice versa, indicating that formation and localisation of an active complex is highly regulated. We are currently investigating the formation of the complex, and its activity at target promoters.
Gene function in spermatogenesis
In 1998 I drew a model of the function of the meiotic arrest genes, in which I postulated that aly would regulate many genes required for spermatid differentiation. This model was based on expression data for about 20 genes. The array experiment was designed to test the model with many more genes. However, the main observation revealed by the array analysis is that we know very little about gene function in Drosophila spermatogenesis. I could initially not answer my question "do the meiotic arrest loci predominantly regulate genes required for spermiogenesis, and not genes required before meiosis?" because the function of the majority of genes that changed significantly in the mutants was not known. We therefore began a large-scale functional-genetics project in which we are using RNA in situ hybridisation to describe the expression pattern, and genetic regulation, of more than 1000 genes in testes. We have examined the expression patterns of about 1200 genes, and it seems my initial prediction was correct – genes that act after meiosis tend to be regulated by the meiotic arrest genes, whereas genes that act earlier tend not to require the meiotic arrest genes for their expression.
Post-meiotic gene expression in Drosophila
It has been generally accepted that there is no post-meiotic transcription in Drosophila spermatogenesis. However, in our in situ hybridisation project, we have identified about 25 genes that are transcribed during the elongation stage of spermatid development. Moreover, their transcripts are localised to the distal ends of the spermatids. The localised transcripts fall into two classes - "cups" and "comets". A mutation in one of the comet genes, scotti, is male sterile, with defects late in spermatogenesis. We are using in vivo reporter constructs and genetic analysis to examine the mechanisms controlling the mRNA and protein localisations and functions.
Watch a video about why sperm are so interesting
Funding
Research in my lab is funded by BBSRC.
Group members
- Dr Katia Jindrich
- Mr Robert Mitchell
Postgraduate research students
- Mr Shrinivas Dighe
- Miss Fiona Messer
- Miss Cristina Fernadez Garcia
Supervision
SWBIO-DTP PhD project available
A video describing the project
I am also willing to consider self-funded applicants to work on aspects of regulation of gene expression, RNA localisation and circRNAs, and stem cells in Drosophila. I would work with the student to define a project of mutual interest.
Project Description for SWBio project
We have discovered a set of localised mRNAs, which are found specifically at the growing ends of Drosophila spermatids, in patterns resembling comets or cups. We also discovered a set of known RNA-binding proteins that also localise to this region. In this project you will investigate potential roles of the RNA-binding proteins in localising these specific mRNAs. RNA localisation and translation will be investigated in RNA-binding protein mutants. Protein- RNA interactions will be assayed in vitro with both purified components and extracts (to allow ternary complex formation). You will also determine whether, and how, mutations in the localised mRNAs and RNA-binding proteins affect the intricate structure of developing spermatid tail tips.
This will provide the basis for a further analysis of this novel and virtually uncharacterised set of localised mRNAs. For example, systems biology and mathematical modelling approaches can be applied once the basic parameters of localisations, using super-resolution methods, and interactions at the biochemical and functional levels have been determined.
Objectives
-To describe and compare the comet and cup mRNAs’, and RNA-binding proteins’, localisations at the growing ends of spermatids.
-To determine whether the known RNA-binding proteins are important for localisation of any comet and cup mRNAs.
-To identify and characterise direct (or indirect) protein-RNA binding interactions between the localised mRNAs and the RNA-binding proteins.
-To investigate whether mutations in comet and cup genes, and the RNA-binding proteins, cause defects in the cellular structure at the growing ends of elongating spermatids.
-To uncover the relationship between "comet" and "cup" transcript localisation patterns.
-To determine whether the known RNA-binding proteins regulate comet and cup mRNA translation.
Eligibility
This studentship is available to UK and EU nationals who have established UK residency (EU nationals must have ordinarily lived in the UK throughout the three years preceding the start of the studentship). Please refer to the DTP eligibility webpage for more details: https://www.swbio.ac.uk/programme/eligibility/
Cardiff University will be able to award up to one fully funded four-year studentship for EU students who do not meet the residency requirements.
Entry requirements
Please refer to the DTP eligibility webpage for academic entry requirements: https://www.swbio.ac.uk/programme/eligibility/
If English is not your first language, you will need to achieve an IELTS score of 6.5 with 6.5 in all skills.
How to apply
Make your application to Cardiff University: https://www.cardiff.ac.uk/study/postgraduate/applying/how-to-apply
Please ensure that your application includes:
Two references. Neither of the referees should be part of the supervisory team.
Academic transcripts / degree certificate(s)
Personal statement. Please include supporting evidence for your Maths background.
Curriculum Vitae (CV)
English language certificates (where applicable)
Please refer to the DTP webpage for information about the selection process: https://www.swbio.ac.uk/programme/selection-process/
Applications must be submitted by midnight on Monday 2nd December 2019.
Funding Notes
This studentship will provide a stipend for 4 years in line with UK Research and Innovation (Research Council) rates (£15,009 in 2019/20), payment of university tuition fees, and a Research and Training and Support Grant (RTSG) to support the project.