Every human cell carries the same DNA, yet a nerve cell and a muscle cell are utterly different—because different genes are switched on at the right time and place during development. The switches are DNA sequences called enhancers, scattered across vast stretches of the genome, often hundreds of thousands of letters apart. Their arrangement—their order, position, and orientation—has been preserved across hundreds of millions of years of evolution, suggesting hidden rules that scientists do not yet understand. This project aims to crack that code, which the team calls “enhancer semantics.” Without it, researchers cannot explain how gene regulation shapes animal evolution or predict which disease-causing mutations disrupt these landscapes. The team will map every enhancer activity at a model gene locus during zebrafish development, build computational models of the design rules, then systematically reorganise enhancer clusters using genome synthesis, and finally test the rules in transgenic zebrafish and mice. This is fundamental science: it asks how complex organisms build themselves from a single genome. If successful, it could transform how scientists interpret the non-coding genome, improve predictions of which mutations cause developmental disorders, and provide a blueprint for engineering synthetic gene circuits.
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The vertebrate body is composed of hundreds of intricately organised cell types, determined not by gene number but by precise gene activation in space and time during development. This regulation is driven by enhancers - gene regulatory DNA sequences that recruit transcription factor proteins to control gene expression. Often dispersed over large distances around genes in what is often called the “dark genome”, dozens of enhancers form large regulatory landscapes, sometimes spanning a megabase (million nucleotides) in size, that coordinate a gene’s activity. The arrangement of enhancers - position, order and orientation - shows remarkable conservation over hundreds of millions of years of evolution, suggesting fundamental yet unexplained rules governing this organisation. Without understanding these principles, we cannot explain how gene expression variation shapes the evolution of animals or predict disease-coding mutations that disrupt regulatory landscapes. While the function of individual enhancers is understood in principle, the significance of their order and orientation remains obscure. Structural genomic rearrangements suggest that the integrity of regulatory landscapes is crucial. Yet transgenic experiments indicate flexibility in enhancer order. These contradictions stem from the technological challenges of studying enhancer function in the context of large, complex genomic regions containing many different enhancers. Our interdisciplinary team has advanced understanding of gene regulatory landscapes. We have refined zebrafish as a vertebrate model for investigating enhancer function. By integrating genome analysis, engineering, and transgenesis with cutting-edge genomics technologies, we have uncovered distinct enhancer activities within large regulatory landscapes and developed methods for large-scale enhancer analysis. Crucially, we have developed synthetic genomics tools to test genome organisation principles. Building on this expertise, our proposal integrates computational analysis, genome synthesis, and transgenic experiments to investigate the rules of enhancer organisation “enhancer semantics” in vertebrate development. Our research is ambitious, timely, and transformative, addressing a fundamental question in developmental and evolutionary biology: How is gene expression regulated across large chromosomal regions? Moving beyond conventional studies, we treat enhancer clusters as functional units rather than isolated elements. By integrating computational and experimental approaches, we aim to uncover the principles of enhancer semantics, driving a paradigm shift in our understanding of gene regulation. We propose a systematic, four-pronged, integrated approach: READ: Generate the first comprehensive, cell-by-cell map of all enhancer activities at a model gene locus throughout zebrafish development. PREDICT: Develop computational models to define the design rules of enhancer semantics and their evolutionary conservation. DESIGN & RE-WRITE: Systematic reorganise enhancer clusters by genome synthesis TEST: Generate transgenic zebrafish and mouse models with synthetic regulatory landscapes to experimentally test enhancer semantics. Our proposal aligns with Frontier Bioscience by pushing the boundaries of gene regulation research at an unprecedented scale. This has broad implications: Advancing Fundamental Knowledge: Deciphering enhancer semantics will shed light on the regulatory logic governing vertebrate development. Biomedical Relevance: Enhancer misregulation is implicated in developmental disorders (‘enhanceropathies’), cancers, and evolutionary change. Understanding these regulatory principles will enhance genome annotations and disease research. Technological Innovation: By integrating genome engineering, multiomics, and synthetic genomics, we are pioneering methodologies with wide applications in biology. Training Future Scientists: This multidisciplinary program will train nine early-career researchers in synthetic genomics, functional genomics, and developmental biology, fostering a new generation of scientists with a constructionist mindset.
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