Prof Anne C Ferguson-Smith

Professor of Developmental Genetics
Department of Physiology, Development and Neuroscience
University of Cambridge

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We are interested in the molecular events governing mammalian development and in understanding situations where normal developmental processes have been disturbed. In particular, our research is directed towards investigating the developmental role of imprinted genes and the mechanism(s) controlling their expression. Genomic imprinting is a remarkable normal process that causes some genes to be expressed solely from maternally inherited chromosomes and others from paternally inherited chromosomes. This means that the egg and sperm contribute unequal functions to the developing conceptus through the parental-origin specific expression of imprinted genes. In mouse and man, disorders can arise when the dosage of imprinted genes is altered through imbalances in the parental-origin of particular chromosomes, by mutations in the single active allele or by mutations affecting the imprint process. One of the key issues in the field is, why did the process of genomic imprinting evolve? Using techniques that combine classical and molecular genetics, we are investigating the developmental consequences of altering the dosage of imprinted genes on mouse chromosome 12. These perturbations result in embryonic lethality and developmental defects; affected tissues include muscle, skeleton and placenta. We have identified imprinted genes on this chromosome and are studying their function both pre and post-natally. We are currently particularly interested in the role of imprinted genes in the control of postnatal metabolic processes. This functional analysis may also contribute to our understanding of why imprinting has evolved.

Genome function is modulated by epigenetic modifications that can affect a number of processes including chromosome architecture and function, chromatin structure and gene expression. During the lifetime of the organism these modifications provide a dynamic, heritable and reversible method to affect genome function without changing the DNA sequence. These epigenetic modifications include DNA methylation, histone modification and it is likely that non-coding RNAs are also involved.It is well-established that epigenetic modifications regulate the parental-origin specific expression of imprinted genes. Most imprinted genes identified to date are located in clusters of maternal and paternally expressed alleles suggesting both short and long range cis-acting epigenetic regulatory features. Imprinted domains are therefore an excellent in vivo model system to investigate the role of epigenetic modification in gene expression. Our scientific aims are:

(a) to identify common features involved in the regulation of imprinted genes, using comparative and functional genomics approaches between multiple imprinted domains in the same species, and the same imprinted domain in different species,
(b) to determine the functional role of imprinted non-coding RNAs. These include large spliced transcripts and small microRNAs.
(c) to contribute insight into how the mechanism of imprinting evolved by assessing the function of common genomic features (including repetitive and retroviral-like sequences) within imprinted domains.
(d) to understand the early epigenetic events involved in nuclear programming in early mammalian embryos.
(e) to conduct a comprehensive analysis that combines comparative sequence analysis
, comparative epigenetic analysis and functional genetic studies in mouse to determine the evolution, organisation, structure, regulatory interactions
, parental-origin specific control and the gene functions of the 1.7Mb genomic region encompassing the imprinted domain on distal mouse chromosome 12.

Techniques include, transgenic/knockout mice, comparative in silico genomic analysis, assays for DNA and chromatin modification, classic and molecular genetics, custom array-based analyses including ChIP on chip.



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