Quantitative regulation of gene expression in single cells

Scott Berry

Group leader

Hi! I am Scott. After completing my undergraduate studies in Theoretical Physics and Biology at the University of Adelaide and the University of Western Australia, I moved to the UK for my PhD at the John Innes Centre. There, I worked with Caroline Dean and Martin Howard, combining theoretical and experimental biology approaches to understand mechanisms of epigenetic memory in Arabidopsis thaliana. I then moved to Switzerland as a HFSP postdoctoral fellow, working with Lucas Pelkmans at the University of Zurich. In Lucas’ group, I shifted model systems from plants to mammalian cells, and became immersed in the wonderful world of modern single-cell biology – focusing on understanding the mechanisms by which cells coordinate gene expression with cell size. Since 2021, I have been a group leader at Single Molecule Science at the University of New South Wales, and also joined the RNA Institute in 2023.

Alexander Gillis

Postdoc

I completed my undergraduate degree with majors in neuroscience and pharmacology. My PhD was undertaken at University of Sydney, working with Prof Macdonald Christie, during which I studied the pharmacology of opioid analgesics across in vitro assays and rodent behavioural studies. In the course of that work, I became interested in mathematical modelling of biological systems as a tool to unpick signalling mechanisms. As part of my PhD, I completed a research period at University of Nottingham, working with Prof Meritxell Canals. There, we sought to examine the kinetics of opioid receptor signalling on a population & single molecule level. As a result of this approach to receptor signalling systems, I have become increasingly interested in using similar techniques to systematically deconstruct other biological pathways.

 a.gillis[at]unsw.edu.au

 @acftbl

Angela Arabiotorre

Postdoc

Howdy! I obtained my bachelor’s degree in Bioanalysis at Central University of Venezuela and was awarded the Outstanding Undergraduate Project certificate for studying molecular diagnostic techniques of Trypanosoma cruzi. I obtained my master’s degree in Molecular Biology and Biomedicine at University of the Basque Country (UPV/EHU) in Spain. At a research placement at Prof Banafshé Larijani’s laboratory in the Biophysics Institute (UPV/EHU), we analysed the phosphoinositide and protein physical proximity through the implementation of FRET microscopy to study the biogenesis of nuclear envelope assembly. I completed my Ph.D. candidacy under the guidance of Prof Vytas Bankaitis and Dr. Aby Grabon at Texas A&M University (USA). There, I described the regulatory role of Phosphatidylinositol-4-phosphate in the dense granule biogenesis and exocytosis in Toxoplasma gondii. I am interested in studying the physiology and biochemistry of eukaryotic cells, including gene expression and inheritance, and how these were shaped through evolution.

 a.arabiotorre[at]unsw.edu.au

 @acftbl

Teddy Cheng Wei Kang

PhD student

Hello, I am Teddy. After completing my undergraduate in Resource Biotechnology at University of Malaysia, Sarawak, I continued my MSc in Molecular Medicine under Dr Oon Chern Ein at Universiti Sains Malaysia. This project involved collaborative work together with researchers at the Karolinska Institutet, aimed at determining if manic fringe protein expression can be utilized as a biomarker for therapeutics and prognosis in kidney cancer, as well as to determine its association with immune cell infiltration. Our research group also collaborated with the Weatherall Institute of Molecular Medicine to further elucidate the expression pattern of manic fringe in blood vessels of renal cancer and in tumor angiogenesis. I am currently a PhD student researching the global control of mRNA metabolism in human cells.

 c.wei_kang[at]unsw.edu.au

Hongpei Li

PhD student

Hello, my name is Hongpei. I completed my undergraduate study in Biological Sciences at Jinan University in China, where I developed a strong interest in synthetic biology. I continued to pursue an MSc in synthetic biology and biotechnology at the University of Edinburgh, where I investigated the sugar consumption strategy in budding yeast using quantitative methods under the supervision of Professor Peter Swain. After completing my MSc, I worked as an R&D trainee at Ailurus Biotechnology, developing a bio-computing platform based on understanding artificial biological processes in E.coli using massively parallel reporter assays. I joined Scott’s group in 2023 as a PhD student and my current research focuses on understanding quantitative epigenetic memory in human cells using synthetic biology tools.

 hongpei.li[at]unsw.edu.au

Bailey Hiles-Murison

PhD student

Hi! My name is Bailey. I completed my undergraduate degree in Molecular Genetics and Biotechnology at Curtin University in 2021, studying honours under Ryu Takechi at Curtin’s Health Innovation and Research Institute. For my honours project I investigated the effects of Probucol on attenuating neurodegenerative changes associated with APOE4 genotype, using both in-vivo and ex-vivo analyses of transgenic mice expressing human APOE isoforms. I also worked on a murine model of traumatic brain injury where we established early neuropathological developments in the context of repetitive sub-concussion. Since beginning my studies I’ve always held a keen interest in cell biology, and I joined Scott’s group in 2023 as a PhD candidate, focusing on visualisation of transcription and mRNA processing in living cells.

 b.hilesmurison[at]unsw.edu.au

 @blymrsn

Open positions

Postdoc / PhD / Honours

Please contact Scott if you are interested in applying. More information on scholarships for Australian and international students can be found here.

We are interested in the mechanisms used by cells to regulate gene-specific and global RNA abundance – ranging from epigenetic memory and cellular decision-making to global RNA metabolism in the context of cellular physiology. We seek to generate a quantitative understanding of these processes.

Our research methodology is a combination of ’top-down’ (data-driven) and ‘bottom-up’ (hypothesis-driven) approaches. We make extensive use of high-throughput microscopy and automated image analysis, which enables detailed measurement of quantitative cellular phenotypes (for example, the abundance and localisations of specific proteins or RNAs) across large cell populations. Resulting datasets are then analysed using a variety of methods from data science. We complement these image-based approaches with functional genomics experiments, based on next-generation sequencing – providing exquisite genomic resolution, and use perturbation experiments including genome and epigenome-editing to test specific hypotheses.

Projects in the lab are often underpinned by construction of minimal mathematical models at the molecular level, which we use as a tool for exploring possible explanations of experimental results and prioritising future experiments.

We believe that the best science happens in the overlap between fields. We strive to build a diverse team and foster collaborations across fields and disciplines.

Stability and plasticity of epigenetic memory

The chromatin of individual genetic loci can be set into molecular ‘states’ that control the expression of the underlying genes, and in some cases even instruct their own inheritance – acting as local epigenetic memory elements. When necessary, however, chromatin can also be reliably switched from one state to another – by processes that involve coordinated changes to the histone modifications, accessibility of regulatory sequences, and expression states of the underlying genes.

We are interested in the interplay between gene-specific diffusible regulatory factors (e.g. transcription factors), which tend to have continuous (analogue) control over gene expression, and heritable chromatin states (e.g. Polycomb-repressed chromatin), which tend to promote bi-modal (digital) stable expression states. To study these processes we use in vitro differentiation of epithelial cells from human induced pluripotent stem cells.

Further reading:
Yang, Berry et al., Science, 2017
Berry et al., Cell Systems, 2017
Antoniou-Kourounioti et al., eLife, 2023

Mechanistic model of self-perpetuating active and repressed chromatin states.

Global control of RNA metabolism

Mammalian cells coordinate RNA production rates with cell size to ensure RNA concentration homeostasis. We discovered that this process relies on adapting transcription rates according to nuclear mRNA concentration, so that overabundance of nuclear mRNA leads to transcriptional repression. This mechanism involves mRNA-based regulation of the activity of RNA Polymerase II, which in turn determines polymerase abundance. We are interested in further dissecting the interplay between the transcriptional machinery, nuclear RNA export and RNA degradation factors that act in concert to ensure robust mRNA concentration homeostasis.

Further reading:
Berry et al., Cell Systems, 2022
Berry et al., Trends in Cell Biology, 2022

High-dimensional cellular phenotyping

In recent years, technological advances have made it possible to visualise tens to hundreds of proteins in single cells. This has brought with it the ability to accurately quantify the high-dimensional relationships between protein abundances and their modification states, as well as the cell-to-cell variability of their subcellular localisation and co-localisation.

We use Iterative Indirect Immunofluorescence Imaging (4i) throughout our research to comprehensively evaluate changes to cellular phenotypes in the context of cellular differentiation and upon perturbation of RNA metabolism. These datasets are extraordinarily rich in information, however much of this information is not easy to interpret using existing approaches. In collaboration with Lucas Pelkmans’ and Fabian Theis’ research groups, we have developed a new computational image analysis workflow called CAMPA to facilitate analysis of these data across different perturbations, at the subcellular, cellular and population scales.

Further reading:
Spitzer, Berry et al., Nat Methods, 2023
CAMPA on GitHub

Preprints

Robust and Versatile Arrayed Libraries for Human Genome-Wide CRISPR Activation, Deletion and Silencing

Yin, J.-A., Scheidmann, M. C., Frick, L., Trevisan, C., Dhingra, A., Spinelli, A., Wu, Y., Yao, L., Vena, D.L., De Cecco, E., Ging, K., Liu, T., Täger, J., Rodriguez, S., Guo, J., Berry, S., Losa, M., Hornemann, S., Kampmann, M., Pelkmans, L., Hoepfner, D., Heutink, P., and Aguzzi, A.
bioRxiv | PDF | bioRxiv

2024

Global control of RNA polymerase II

Gillis, A., and Berry, S.
BBA Gene Regulatory Mechanisms | PDF | Journal

2023

Integrating analog and digital modes of gene expression at Arabidopsis FLC

Antoniou-Kourounioti, R.L.*, Meschichi, A.*, Reeck, S.*, Berry, S., Menon, G., Zhao, Y., Fozard, J., Holmes, T., Zhao, L., Wang, H., Hartley, M., Dean, C., Rosa, S., Howard, M. eLife | PDF | Journal | bioRxiv
* Equal contribution

Learning consistent subcellular landmarks to quantify changes in multiplexed protein maps

Spitzer, H.*, Berry, S.*, Donoghoe, M., Pelkmans, L. and Theis, F.
Nature Methods | PDF | Journal | Research Briefing | bioRxiv | GitHub | Read the Docs
* Equal contribution

2022

Mechanisms of cellular mRNA transcript homeostasis

Berry, S., and Pelkmans, L.
Trends in Cell Biology | Journal

Feedback from nuclear RNA on transcription promotes robust RNA concentration homeostasis in human cells

Berry, S.^, Müller, M., Rai, A. and Pelkmans, L.^
Cell Systems | PDF | Journal | bioRxiv
^ Corresponding authors

2021

High content genome-wide siRNA screen to investigate the coordination of cell size and RNA production

Müller, M., Avar, M., Heinzer, D., Emmenegger, M., Aguzzi, A., Pelkmans, L.^, and Berry, S.^
Scientific Data | PDF | Journal | Data
^ Corresponding authors

2017

Disruption of an RNA-binding hinge region abolishes LHP1-mediated epigenetic repression

Berry, S., Rosa, S., Howard, M., Bühler, M., and Dean, C.
Genes & Development | PDF | Journal

Slow Chromatin Dynamics Allow Polycomb Target Genes to Filter Fluctuations in Transcription Factor Activity

Berry, S., Dean, C., and Howard, M.
Cell Systems | PDF | Supplementary | Journal | Commentary

Distinct phases of Polycomb silencing to hold epigenetic memory of cold in Arabidopsis

Yang, H.*, Berry, S.*, Olsson, T.S.G., Hartley, M., Howard, M., and Dean, C.
Science | PDF (accepted version) | Journal
* Equal contribution

2015

Local chromatin environment of a Polycomb target gene instructs its own epigenetic inheritance

Berry, S., Hartley, M., Olsson, T.S.G., Dean, C., and Howard, M.
eLife | PDF | Journal

Environmental perception and epigenetic memory: mechanistic insight through FLC

Berry, S., and Dean, C.
The Plant Journal | PDF | Journal

2014

Lipopolysaccharide O antigen size distribution is determined by a chain extension complex of variable stoichiometry in Escherichia coli O9a

King, J.D.*, Berry, S.*, Clarke, B.R., Morris, R.J., and Whitfield, C.
Proceedings of the National Academy of Sciences | PDF | Supplementary | Journal
* Equal contribution

2012

Illustrations of Mathematical Modeling in Biology: Epigenetics, Meiosis, and an Outlook

Richards, D.*, Berry, S.*, and Howard, M.
Cold Spring Harbor Symposia on Quantitative Biology | PDF | Journal
* Equal contribution

2011

qwViz: Visualisation of quantum walks on graphs

Berry, S.D., Bourke, P., and Wang, J.B.
Computer Physics Communications | Journal

Two-particle quantum walks: Entanglement and graph isomorphism testing

Berry, S.D., and Wang, J.B.
Physical Review A | Journal

2010

Quantum-walk-based search and centrality

Berry, S.D., and Wang, J.B.
Physical Review A | arXiv | Journal