Anne C Ferguson-Smith, PhD
Professor of Developmental Genetics Tel: +44 (0)1223 333834(office) 333844 (lab), Fax: +44 (0)1223 333840, E-mail: afsmith@mole.bio.cam.ac.uk
Associate Member of the EU Epigenome network of excellence, see www.epigenome-noe.net for details.
Vacant Marie Curie PhD studentship – Epigenetics - Sept 2012
1) Genomic imprinting in mammalian development & human disease.
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.
2) Epigenetic control of genome function.
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.
Research Team:
Sarah Allen
Marika Charalambous, PhD
Carol Edwards, PhD
Dionne Gray
Isabel Gutteridge
Mitsuteru Ito, PhD
Kirsten McEwan
Lizzie Radford
Rebecca Rancourt
Sacramento Rodriguez-Ferron, PhD
Miguel Soares, PhD
Li X, Ito M, Zhou F, Youngson N, Zuo X, Leder P, Ferguson-Smith AC. A maternal-zygotic effect gene Zfp57 maintains both maternal and paternal imprints. The evolution of the imprinted Dlk1-Dio3 domain in mammals. Developmental Cell 15 547-557(2008)
Edwards C, Mungall A, Matthews L, Ryder E, Gray DJ, Pask AJ, Shaw G, Graves JAM, Rogers J, Dunham I, Renfree MB, Ferguson-Smith AC. The evolution of the imprinted Dlk1-Dio3 domain in mammals. PLoS Biology 6(6):e135 (2008)
Kagami M, Sekita Y, Nishimura G, Irie M, Kato F, Okada M, Yamamori S, Kishimota H, Nakayama M, Tanaka Y, Matsuoka K, Takahashi T, Noguchi M, Tanaka Y, Masumoto K, Utsonomiya T, Kouzan H, Komatsu Y, Ohashi H, Kurosawa K, Kosaki K, Ferguson-Smith AC, Ishino F, Ogata T. Deletions and epimutations affecting the human chromosome 14q32.2 imprinting region: implications for imprinting control and phenotypic development in paternal and maternal uniparental disomy for chromosome 14. Nature Genetics, 40(2):237-42 (2008).
Lin SP, Coan P, Teixeira da Rocha S, Seitz H, Cavaille J, Takada S, Ferguson-Smith AC. Consequences of loss of imprinting at the mouse Dlk1-Dio3 imprinted domain differ between embryo and placenta. Development 134(2): 417-426 (2007)
Coan P, Conroy N, Burton G & Ferguson-Smith AC. Origin and characteristics of glycogen cells in the developing murine placenta. Developmental Dynamics 235(12): 3280-3294 (2006).
Rugg-Gunn P, Ferguson-Smith AC, Pedersen R. Epigenetic status of human embryonic stem cells. Nature Genetics 37(6) 585-587 (2005).
Seitz H, Royo H, M-L Bortolin, Lin S-P, Ferguson-Smith AC, Cavaille J. A large imprinted microRNA gene cluster at the mouse Dlk1-Gtl2 imprinted domain. Genome Research 14(9) 1741-1748 (2004).
Seitz, H., Youngson, N., Lin, S-P, Dalbert S., Paulsen, M., Bachellerie J-P, Ferguson-Smith AC#, Cavaille J# Imprinted microRNAs transcribed antisense to a reciprocally imprinted retrotransposon-like gene. Nature Genetics 34(3) 261-262 (2003).
Lin S-P, Youngson N, Takada S, Seitz H, Reik W, Paulsen M, Cavaille J, Ferguson-Smith AC. Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1-Gtl2 imprinted cluster on mouse chromosome 12. Nature Genetics 35 (1) 97-102 (2003)
Recent Reviews:
Teixeira Da Rocha S, Edwards C, Ito M, Ogata T, Ferguson-Smith AC. Genomic imprinting at the mammalian Dlk1-Dio3 domain. Trends in Genetics (2008) in press
Charalambous M, Teixeira da Rocha S, Ferguson-Smith A. Genomic imprinting, growth control and the allocation of nutritional resources - implications for post-natal life. Current Opinion in Endocrinology, Diabetes and Obesity, 14(1) 3-12 (2007).
Rugg-Gunn P, Ferguson-Smith AC, Pedersen R. Status of genomic imprinting in human embryonic stem cells as revealed by a large cohort of independently derived and maintained lines. Human Molecular Genetics (2007) 16 R243-251.
Edwards CA, Ferguson-Smith AC. Mechanisms regulating imprinted genes in clusters. Current Opinion in Cell Biology 19(3) April 26 (2007).