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Anne C Ferguson-Smith PhD FMedSci

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Wellcome Trust Senior Investigator, Professor of Genetics
Tel: +44 (0)1223 333834 (office) 333844 (lab), Fax: +44 (0)1223 333840, E-mail: afsmith@gen.cam.ac.uk
Anne is a member of the Centre for Trophoblast Research.

Reseach Summary
Our lab focuses on the molecular events governing pre- and post-natal mammalian development. Our research is directed towards investigating the developmental role of imprinted genes and the epigenetic mechanism(s) controlling their parental-origin specific expression and applying this information to understanding epigenetic control and the regulation of developmental processes in a wider context.

Genomic imprinting and parental-orgin effects

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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. Over the years we and others have contributed to understanding aspects of genomic imprinting including the epigenetic mechanisms that programme functional differences between the two parental chromosomes and generate a heritable memory of parental origin. In addition we have explored the function of imprinted genes in development and disease and the evolution of imprinting and its epigenetic control. Much of our work has focused on the Dlk1-Dio3 imprinted domain on mouse chromosome 12 which contains paternally expressed protein coding genes and multiple non-coding RNAs expressed specifically from the maternally inherited chromosome (Fig. 1).

Current research themes
More recently we have been using genomic imprinting as a paradigm for understanding aspects of genome function and its epigenetic control in a wider context.  Our current programme is divided into three integrated research themes.

1. Stem cells and the epigenetic programme in vitro and in vivo
2. Functional genomics and epigenomics
3. Development, environment and disease

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1. Stem cells and the epigenetic programme in vitro and in vivo
In this area, we explore the factors required for the establishment and maintenance of epigenetic states in embryonic stem cells, in iPSCs in culture and in progenitor cells and developing organ systems in vivo. We study developmental contexts in which genomic imprinting can be used as a developmental switch to control gene dosage and the consequences for the stem cell niche when this process goes wrong (Fig. 2).

2. Functional genomics and epigenomics
Here we study the function, epigenetic regulation and evolution of genomic features including repetitive sequences, regulatory elements and non-coding RNAs and their contribution to the regulation of genome function. This involves the use of genome-wide next generation sequencing technologies to functionally characterise epigenomes combined with more detailed targeted approaches investigating functional genomics. We are particularly interested in genotype-epigenotype interactions and their impact on phenotype.

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3. Development, environment and disease
It is often assumed that epigenetic states mediate signalling between the environment and the genome. If true, this has major implications for health and disease. The role of dynamic changes in the epigenetic programme that influence intrinsic developmental processes is well-recognised, but genomic mechanisms by which external environmental signals can influence changes in developmental or adaptive processes are not fully understood. We are exploring the epigenetic control of gene dosage and its influence on developmental and adult phenotypes in a range of genetic and environmentally perturbed model systems. In addition, we are addressing the function of imprinted coding genes and of large and small imprinted non-coding RNAs, including microRNAs. These studies are providing insights into the role of imprinted genes in the regulation of normal development and in postnatal adaptations such as the transition to independent life (Fig. 3).

Technical approaches include: transgenic/knockout mice, developmental and phenotypic characterisation including morphometrics, stereology and histology, whole genome epigenomics, comparative in silico genomics and bioinformatics including for the analysis of genome-epigenome interactions, assays for DNA and chromatin modification including chromatin immunoprecipitation, chromatin conformation studies, classic and molecular genetics, metabolic physiology and neurodevelopmental studies.

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Research Team

Research Associates
Mitsu Ito PhD
Angela Noon PhD
Lizzie Radford MB PhD
Ruslan Strogantsev PhD
Nozomi Takahashi PhD

Carol Edwards PhD (in silico genomics)
Nic Walker PhD (bioinformatics)
Hui Shi PhD (bioinformatics)
Dionne Gray (Lab Manager)

Graduate Students
Sarah Allen
Mary Cleaton
Norah Fogarty (joint with Prof Burton, CTR)
Ben Shaw
Björn þór Aðalsteinsson

Research Assistant staff
Jennifer Corish
Fran Dearden

Affiliated members
Erica Watson PhD (Next Generation Research Fellow – Centre for Trophoblast Research)
Marcela Sjoberg PhD (Research Associate)
Nisha Padmanabhan (PhD student)
Maria Andrenia Bruni (Vargas Scholar)

Current funding sources: Wellcome Trust, MRC, Technology Strategy Board, EU-FP7 EpigeneSys, EU-FP7 BLUEPRINT, EU-FP7-EpiHealth and CTR.

Selected Publications

Selected recent publications (full publication list)
Charalambous M, Teixeira da Rocha S, Rowland T, Ferron S, Ito M, Radford E, Schuster Gossler K, Hernandez A, Ferguson-Smith AC. Imprinted gene dosage is critical for the transition to independent life.
Cell Metabolism 15(2) 209-221 (2012).

Radford EJ, Isganaitis E, Jiminez-Chillaron J, Schroeder J, Andrews S, Didier N, Charalambous M, McEwen K, Marazzi G, Sassoon D, Patti MR, Ferguson-Smith AC. An unbiased assessment of the role of imprinted genes in an intergeneration model of developmental programming.
PLoS Genetics 8(4) e1002605 (2012).

Messerschmidt D, DeVries W, Ito M, Solter D, Ferguson-Smith AC, Knowles BB. Trim28 is required for epigenetic stability during oocyte to embryo transition.
Science 335(6075) 1499-1452 (2012)

Ferron S, Charalambous M, Radford E, McEwen K, Wildner H, Hind E, Morante-Redolat J, Laborda J, Guillemot F, Bauer S, Farinas I. Ferguson-Smith AC. Postnatal loss of Dlk1 imprinting in stem cells and niche-astrocytes regulates neurogenesis.
Nature 475: 381-385 (2011).

Rens W, Wallduck M, Lovell F, Ferguson-Smith MA, Ferguson-Smith AC. Epigenetic modifications on X chromosomes in marsupial and monotreme mammals and their implications for the evolution of dosage compensation.
Proc Natl Acad Sci (USA) Oct 12;107(41):17657-17662 (2010)

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.
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)

Reviews and commentaries
Grossniklaus U, Kelly B, Ferguson-Smith AC, Pembrey M, Lindquist S (2013) Transgenerational epigenetic inheritance: how important is it?
Nature Reviews Genetics
14:228-235.

Ferguson-Smith AC. Genomic imprinting: the emergence of an epigenetic paradigm.
Nature Reviews Genetics 12(8) 565-575 (2011).

Ferguson-Smith AC and Patti ME. You are what your dad ate.
Cell Metabolism 13: 115-117 (2011).

Teixeira Da Rocha S, Edwards C, Ito M, Ogata T, Ferguson-Smith AC. Genomic imprinting at the mammalian Dlk1-Dio3 domain. Trends in Genetics 24:(6) 306-316 (2008).

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).

Edwards CA, Ferguson-Smith AC. Mechanisms regulating imprinted genes in clusters.
Current Opinion in Cell Biology 19(3) April 26 (2007).


Updated 14th September 2012