Research

Cell expression heterogeneity impact on environmental response

Linking heterogeneity in gene expression within individual cells with whole organism phenotypes and adaptability.

Project Summary.

Funding:

This research is supported by the UKRI Biotechnology and Biological Sciences Research Council (BBSRC).

Earlham Institute Strategic Programme Grant Cellular Genomics BBX011070/1 and its constituent work package BBS/E/ER/230001C.

Most of our understanding of gene expression comes from analyses of tissues or even whole organisms. This averages the response of millions of cells, masking important biological responses occurring within individual cells and cell-types.

Single-cell genomics technologies have enabled the analysis of the genomes, epigenomes, and transcriptomes of individual cells at scale. These approaches have highlighted the extent to which the genome functions differently between cells of the same organism during the healthy lifespan.

In multicellular organisms, cell-type specific expression profiles are essential to defining both cellular and organismal phenotypes. Even subtle changes to gene expression in individual cells can have wide-reaching impacts for the fitness of the whole organism.

Using the latest experimental and computational approaches, we aim to reveal how cell expression heterogeneity contributes to cellular and organismal responses to environmental changes, stress, and disease.

Detail

Details.

Understanding cellular identities

Our aim is to gain an understanding of how changes in individual cells can lead to changes in the fitness and health of an organism - be it plant, animal, or human - to define healthy and unhealthy states in organs and tissues.

To do this, we need to understand the molecular differences between cells and be able to measure and analyse the ways in which cells adapt to changes in their environments.

We will advance single-cell technologies for lineage tracing, single-cell multi-omics, and apply numerical ecology to define cell types.

With The Alan Turing Institute we will develop machine learning approaches to characterise cell types and reconstruct cell-specific regulatory networks to identify network rewiring during cellular differentiation.

Uncovering the functional relevance of alternative splicing

A major focus of our work is on the implementation of long-read sequencing to explore alternative splicing in individual cells.

This involves parallel experimental and computational method development for the characterisation of splicing events in single cells, in particular focusing on characterising events that show evidence of regulation during cellular differentiation and ageing.

Using long-read sequencing protocols and associated computational pipelines, we will annotate, quantify alternative splicing, and reconstruct regulatory networks at the transcript level, gaining new insights into how alternative splicing impacts cellular phenotype and function

Uncovering the cell-type specific origins of valuable traits

We are investigating how cellular heterogeneity contributes to phenotypes relevant to agriculture and aquaculture, with the aim of identifying markers associated with valuable traits for breeding or engineering climate-resilient varieties.

Using single-cell and spatial transcriptomics approaches, we are exploring plant cell responses to environmental change and developing tissues in bread wheat (in collaboration with the BBSRC-funded cross-institute programme Delivering Sustainable Wheat). This work is also being applied to crop traits - such as yield and grain size and density - with our industrial partners.

With collaborators at the Roslin Institute and WorldFish, we are characterising the genetic bases associated with environmental resilience and pathogen resistance in tilapia.

Collaborators

Impact statement.

We’re developing and implementing advanced single-cell and spatial transcriptomic approaches to explore gene expression in individual cells within both plant and animal systems.

By applying these approaches in areas of fundamental biology relevant to human health, aquaculture, and agriculture, we will reveal the mechanisms that these systems use to adapt to challenges.

Through close linkage to the National Bioscience Research Infrastructure in Transformative Genomics, these technologies are being made available to the wider bioscience community, facilitating impact in academia and commercial research.