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Regulatory interactions and Complex Phenotypes

Reference	BBS/E/T/000PR9819
Principal Investigator / Supervisor	Professor Anthony Hall
Co-Investigators / Co-Supervisors	Dr Iain Macauley, Dr Nicola Joan Patron, Prof. Christopher Quince
Institution	Earlham Institute
Department	Earlham Institute Department
Funding type	Research
Value (£)	6,572,416
Status	Current
Type	Institute Project
Start date	01/04/2017
End date	31/03/2023
Duration	59 months

Abstract

Deciphering the sources and mechanisms of variation in regulation of genes and genomes is pivotal for understanding the genotype-to-phenotype relationship underlying adaptation, evolution and health. We will integrate genetic studies with transcriptomics, epigenomics and proteomics to generate regulatory and protein-protein interaction networks, to perform systems-level analyses, and to identify and validate molecular drivers of cellular, tissue- and organism-level functions. To better understand the architecture of regulatory circuits in key relevant genomes, we will profile cis-regulatory elements and assess transcriptional regulation to deliver a systems-level view of entirely inferred networks initially in microbial species, followed by vertebrate organisms and then in more complex plants. To better understand the interplay between genetic divergence and gene network evolution, we will compare (species-specific and tissue-specific) reconstructed regulatory networks of aquatic species (Tilapia) and crop species (starting with Arabidopsis thaliana as a model) to predict novel functions, interactions, and further candidate genes that can be collaboratively validated through genome manipulation techniques. For this, we will select species and lines that best represent the existing diversity and physiology for interrogating the fundamental molecular processes of trait and phenotype evolution. We will integrate a variety of data including genomic data, transcriptomics, interactome data, and chromatin data (ATAC-Seq), to investigate the evolution of regulatory networks and regulatory genes, and the role of regulatory networks and pathways in adaptation in the context of domestication. Leveraging on our multi-disciplinary expertise, including our network reconstruction algorithms, and our DNA synthesis capability, we will apply a multi-scale approach to investigate the complexity of host-microbe interactions for both pathogenic and beneficial microbes. Our approach will include the following: 1) state-of-the-art and novel computational biology omics data analysis and network reconstruction methods, 2) in silico modelling of the host-microbe connections for multiple species/strains and conditions, and 3) validation of predictive systems models with synthetic biology approaches. The resulting host-microbe interactions will be used to provide an improved understanding of the mechanisms and systems-level functions of these cross-kingdom connections that are essential for host health and antimicrobial defence mechanisms. As a complementary EI-QI joint effort, we will work with Simon Carding and other QI Research Leaders in the Gut Microbes and Health ISP to produce new fundamental insights into how the gut functions as an integrated organ system and how commensal microbes influence host homeostasis and metabolic health. In particular, we will investigate putative molecular mediators of signalling in enteric neuronal and endocrine cells, which could affect brain function (e.g. appetite control and food preferences). To uncover the mechanisms of these microbial influences on the host, we will predict and map the direct molecular interactions between gut microbes and intestinal epithelial cells as well as the subsequent inter-cellular signalling pathways between epithelial cells (primary site) and cells of the enteric nervous system (secondary sites) affected indirectly by the microbes. Bacterial influence will be modelled and key connections tested using a synthetic biology approach to obtain insights into how certain microbes affect systemic health through cross-kingdom communications in the intestinal tract.

Summary

unavailable

Committee	Not funded via Committee
Research Topics	Animal Health, Crop Science, Microbiology, Plant Science, Synthetic Biology, Systems Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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