BBSRC Institute Strategic Programme: Cellular Genomics (CELLGEN) - Partner Grant

Cells are a fundamental unit of biology and cellular heterogeneity is a hallmark of multicellular life. Within an organism -plant, animal or human - cells can display enormous functional diversity, fulfilling distinct roles that underpin the overall function of the organism. The diversity of cell function reflects distinct "molecular cell identities", emerging from variation in the genomes of each cell, how they are regulated, and the genes they express. Incorporating a cellular perspective into functional genomics experiments is therefore key to unravel how variation in sequence and regulation of the genome within an organism can contribute to its overall function and phenotype. The Cellular Genomics programme (CELLGEN) builds on EI expertise in data science, bioinformatics and single-cell analysis to investigate the impact of genomic and transcriptomic heterogeneity in healthy plants and animals.

Recent developments in molecular and computational science have ushered in an era of single-cell genomics, in which the analysis of the genomes, epigenomes and transcriptomes of individual cells can readily be analysed. In several model systems, these approaches have highlighted the extent to which genome function - but also genome sequence - can vary between cells of the same organism during the healthy lifespan. Here, we seek to leverage and develop these approaches to explore the origins and consequences of genomic and transcriptomic heterogeneity within model and non-model organisms.

These analyses generate high-value, highly-dense datasets, and our programme takes a data-science led approach. Our programme of work leads with WP1 "Data Science for Cellular Genomics" which develops approaches to curate and harmonise datasets, to enable reproducibility, reusability, comparison, and most importantly integration across studies.

WP2 "Consequences of somatic mutations on traits" investigates the diversity and consequences of intraorganismal genomic variation. We will develop approaches to measure emerging genomic heterogeneity (tandem repeats and polyploidisation) and their immediate and long term effects on gene and isoform expression in cells - using model cell lines or primary polyploid cells from plants (trichomes) and mouse (megakaryocytes). We will test novel hypotheses about the relationship between cellular genomic variation and the wider phenotype of the organism, for example measuring the impact of genetic variation between individual cells on gene regulation. This can then be directly related to how genes are expressed at the tissue and whole organism levels.

WP3 "Cellular heterogeneity and expression regulation" characterises cellular transcriptomic heterogeneity and its impact on cell and organism responses to the environment. Here we will explore the regulation of gene expression in plant and animal models of cell lineage commitment (haematopoiesis) and responses to environmental challenges (fish, plant) and dietary intervention.

This programme of work will enable researchers working on diverse biological systems to work synergistically to explore common themes across the tree of life. It will position EI as a world leader in single-cell developments for non-model organisms, plants and animals, going beyond cell-type classification and delivering novel approaches for scalable cellular functional genomics underpinned by advanced data science approaches. By exploring consequences of genomic and transcriptomic variation during a healthy lifespan and into how cellular diversity underpins organismal adaptation to environment, CELLGEN will generate new insights into the rules of life

This project represents the University of Cambridge contribution to the delivery of the Institute Strategic Programme Grant CELLGEN, REFERENCE BB/X011070/1.

Dr James Locke (JL) will contribute to Work Package 2, The Cellular Genome, working on developing mathematical models to investigate plant clock rhythms at the single cell level, as well as collaborating on developing stochastic models of the role of alternative splicing and ploidy in gene regulation. His work in the CELLGEN ISP aligns with his background working on the mechanisms and functions of noisy and dynamic gene regulation. Work from his group has used a combination of modelling and experiment to reveal how noise in gene expression can impact on key cellular properties such as growth, can enable random patterns of giant cells in plant sepals, as well as allow new regulatory strategies. He has also revealed mechanisms for coordination of clock rhythms in the plant clock by examining rhythms at the single cell and sub-tissue level.

In this project, he will build on his prior collaboration with Prof. Anthony Hall (AH) at the Earlham Institute on tracking clock rhythms at the single cell level to understand the design principles of dynamic gene regulation. In Deliverable 3.3, JL and AH will use a combination of transcriptomics (both single cell and spatial) and modelling to construct a spatial model for Arabidopsis that will enable us to investigate regulatory networks across cell types and time and explore heterogeneity in clock function. We will then extend our approach to Wheat, where we will use modelling and experiment to investigate differences in clock regulation in Wheat source and sink tissues. We will build clock models, analyse heterogeneity and contrast with Arabidopsis. JL will also collaborate in other areas of the work package where noise in gene expression plays a role. For example, he will investigate the effects of stochasticity in Alternative Splicing events (Deliverable 3.2.1).