Science for Health
The early development of the human embryo is an extraordinarily dynamic and exquisitely controlled process. At the molecular level, events are orchestrated by a large repertoire of transcription factors, proteins that bind to regulatory regions in genomic DNA to control gene expression. Mutations in these regulatory regions can lead to developmental anomalies and disease. Many of the patterning events that occur are common to all vertebrates as are the transcription factors and interestingly, some of the regulatory code embedded in the genome. However, the protein:DNA interactions are poorly understood, as are the functional effects they mediate.
We take a ‘systems level’ approach to decipher the language and grammar that is encoded in regulatory DNA, particularly that fraction that is common to all vertebrates, and which therefore directs some of the most fundamental aspects of vertebrate embryogenesis. We do this by combining computational approaches with functional assays in zebrafish embryos, an important and tractable model for this sort of work. Once we identify specific regulatory patterns, we can search for these throughout the genome, thereby predicting other regulatory regions. It is important that we know where these regions are in the genome, and what processes they define, as mutations in them can lead to developmental disorders and genetic disease.
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A. Plot of non-coding sequence conservation between mammals and fish across a 3.5 Mb region of human chromosome 15q14, encompassing the Meis2 and c15orf41 genes. Each vertical bar within the blue panel represents a CNE. B. MLAGAN alignment of the c15orf41 locus enclosed by rectangle in A. Human (Hu), mouse (Mu) and lamprey (La) genomic regions are aligned with the orthologous reigon in the Fugu genome. Exons are annotated and represented by mauve peaks (black arrows) and are detectable in all species. Pink peaks represent non-coding conservation. A number of these are conserved in lamprey (blue arrowheads) but a number are also absent (grey arrowheads).
Lateral views. (A) GFP expression at 30 hpf can be seen in the entire nervous system. (B-G) GFP expression in sensory organs and spinal cord at 52 hpf. GFP is expressed in the olfactory bulb (ob) (B), the lens (C), the ear (D), the lateral line (la) (E), the floor plate (fp) (F) and in a circumferential descending interneuron (G) characterised by a major descending axonal branch (da) from which a secondary ascending axonal branch (aa) emerges. The cell body is indicated by an asterisk.
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