Epigenetics & the Dynamic Genome
30 June - 2 July 2005
Cambridge, UK

Organisers:

Anne Corcoran, Babraham Institute, Cambridge, UK
Gavin Kelsey, Babraham Institute, Cambridge, UK
Peter Fraser, Babraham Institute, Cambridge, UK
Wolf Reik, Babraham Institute, Cambridge, UK

Report

Summary

This meeting brought together about 170 scientists from all over the world working on epigenetics and related topics, and was held at the Babraham Institute in Cambridge, and Homerton College Cambridge. The meeting was supported by the Babraham Institute, ESF, The Epigenome NoE in the EU Framework 6 programme, Abcam, Upstate, Diagenode, and the Genetics Society. The 42 international speakers presented their latest, and often unpublished, results on epigenetics and genome dynamics. Prominent themes at the meeting were chromatin organisation and gene expression, stem cells, reprogramming, and cell plasticity, chromosome dynamics and higher order structure, DNA dynamics and repair, imprinting and development, and epigenomics and disease.
There was a keynote lecture on nuclear reprogramming in Xenopus, given by Sir John Gurdon. Representatives from industry and science journalists attended, and a meeting report will be published in Genome Biology. Thanks to the excellence of the speakers and participants, and the generous support from ESF and other sponsors, this was an excellent and highly successful meeting.

Scientific Content

Epigenetics has in the last 5 or so years progressed from an interesting phenomenon to one of the central exciting disciplines in postgenomic biology. With sequences of many animal and plant organisms in hand, the unravelling of transcription factor networks together with various layers of epigenetic information in the genome is critical for our understanding of how organisms develop, and how the genome functions and misfunctions in adults. DNA methylation, histone tail modifications, other chromatin proteins, and nucleosome remodelling complexes, have all been shown to be vital for the regulation of gene expression, and development and differentiation. More recently, epigenetic marks have also been found to play important roles in DNA replication and in genome repair. Finally, methods are being developed for large scale epigenomic analysis of methylation and chromatin marks.

We thus decided to organise the 2nd Babraham Symposium along the lines of these exciting developments, paying particular attention to mechanistic or biological links between different areas. A full programme is appended to this report. In the first session, chromatin patterns in the genome, their assembly, regulation, and functions in the regulation of imprinting and tissue regeneration, were discussed. Of particular importance was the question of whether the large number of existing histone modifications really established a 'code' (Turner), how chromatin domains are established by replication dependent and independent factors (Almouzni) and by the incorporation of histone variants (Henikoff), how tandem repeats in the genome can interact in trans and can cause heritable gene silencing (Chandler), how methylation on histone tails can be reversed by a demethylase (Shi), and how isomerisation of an amino acid in a histone can affect gene expression (Kouzarides). The last two talks in this session dealt with the regulation of genomic imprinting in the placenta by histone methylation in addition to DNA methylation (Feil), and the demonstration that the chromatin protein polycomb is involved in the regulation of tissue regeneration in Drosophila (Paro).

The session on cell plasticity was opended by a Keynote lecture given by Sir John Gurdon. Gurdon described his early nuclear transplantation experiments in Xenopus that demonstrated that differentiated cells could be reprogrammed in the egg cytoplasm, and talked about molecular experiments involving demethylation to unravel the mechanisms involved in reprogramming. This was followed by two talks on factors such as Oct4, Nanog, and Sox2 which are needed for pluripotency of ES cells, and are often deregulated in cloned embryos (Jaenisch), as well as the derivation of neural stem cells from both fetuses and adults, which can be used for tissue transplantation into the brain (Smith). Surani showed that a specific protein factor, Blimp1, was required for the specification of early germ cells in mice, and Sasaki demonstrated the requirement of the de novo methyltransferase Dnmt1 for imprinting in the male and female germline. Torres-Padilla suggested the possibility that chromatin remodelling factors such as Brg1 could be associated with the activation of the embryonic genome in mice, and Dean showed that vernalisation in Arabidopsis was regulated by long-term epigenetic silencing of the FLC gene.

The session on chromatin dynamics was opened by Peter Cook who first proposed the existence of transcription factories; he suggested that physical properties of the DNA could lead to looping involved in gene regulation. The next four talks were concerned with the role of noncoding RNA in epigenetic regulation. Corcoran reported her work showing association of intergenic non-coding RNA with VDJ recombination of immunoglobulin genes, while Brockdorff and Avner talked about X chromosome inactivation which requires the non-coding RNA transcript Xist. Brockdorff showed that the incomplete spreading of inactivation into autosomes (in X-autosome translocations) could be explained by relative depletion on autosomes of repetitive elements, while Avner showed that imprinted X inactivation was relatively unstable in trophectoderm stem cells. Finally, Barlow demonstrated that the non-coding RNA Air and histone modifications play a role in imprinting of the Igf2r gene. The next two talks were on higher order chromatin regulation, with the observation that genes on different chromosomes can interact in trans in transcription factories (Osborne), and that chromosome looping between regulatory PRE elements may be important for regulation of Hox genes in Drosophila (Lanzuolo). The final two talks in this session dealt with imprinting in plants, with the demonstration that the gene Demeter which regulates imprinting of Medea, is likely to be a 5-methylcytosine glycosylase that excises the modified base from DNA (Fischer), and that imprinting of the polycomb gene Medea in turn regulates imprinting of a downstream gene, Pheres (Grossniklaus).

The session on DNA dynamics and repair began by Verreault demonstrating that a specific histone tail mark, histone H3 lysine 56 acetylation, was important for regulating the response to strand breaks in the DNA, and Varga-Weisz suggesting a model for epigenetic inheritance of chromatin states by nucleosome remodelling factors being coupled to DNA replication. Petersen-Mahrt revealed that cytosine deaminases such as Aid can also deaminate 5-methylcytosine, suggesting a role in epigenetic reprogramming and in mutations in cancer. Lindahl reviewed various repair pathways in mammalian cells, and how they are potentially connected to the removal of modified bases, while Schaer showed that a mismatch repair enzyme, TDG, has a role in regulating gene expression.

Talks by young scientists that were selected from abstract submissions followed in the next session (some of these were also interspersed with talks in other sessions). Sutherland suggested that KRAB zinc finer proteins repress genes by recruiting them to nuclear foci that may act as silencing factories. Roguev described surprising differences between related chromatin complexes in the two yeasts, S cerivisae and S pombe, while Uchiyama analysed the protein composition of human metaphase chromosomes, and Gutierrez-Triana described the evolution of proteins related to DNA methylation in nematodes, which have lost DNA methylation. Finally, Kanduri described a cell culture system in which he showed that the Kcnq1ot1 antisense RNA had a role in gene silencing in cis.

The final two sessions dealt with developmental or disease consequences of normal or abnormal epigenetic regulation. Ferguson-Smith showed a series of transgenic experiments in which she showed that the imprinted gene Dlk1 was involved in regulation of muscle and fat metabolism, while Isles presented a model whereby environmental influences before and after birth could lead to epigenetic programming with long-term effects on adult behaviour. Scott looked at developmental effects of chromosome imbalances in Arabidopsis and suggested they could be explained by genetic conflict and imprinting, while Kelsey also explored the theory of genetic conflict in describing imprinting system that antagonistically regulate postnatal physiological adaptations. Bonthron continued this theme by showing how specific or genome wide alterations of imprinting in humans could lead to various diseases, and Mungall described efforts by the Sanger Institute to sequence most imprinted regions in different mammalian clades in order to understand the evolution of imprinted genes. Mertens described an interesting mechanism of gene silencing in a tumour suppressor gene, while Schuebeler revealed a new method for the genome wide analysis of DNA methylation which he applied to cancer. Finally, Martienssen described novel polymerases which are involved in RNAi mediated heterochromatisation and gene silencing.

There were many occasions for attendants to interact informally during the meeting, including a dinner in the marquee at the Babraham Institute, and a dinner followed by a dance at Chilford Hall in Linton.

The meeting was followed on Sunday morning by a EU sponsored workshop on imprinting and X chromosome inactivation, for which a number of participants stayed at the Institute.


Assessment of the results and impact of the event on the future direction of the field

The organisers feel that this was a very successful meeting, and this was the result of having internationally leading speakers, a lot of unpublished material presented, bringing together new areas of work for the first time, and also the location of the Conference at the Babraham Institute with excellent conference facilities and a beautiful setting in the countryside just outside Cambridge. This contributed to the relaxed and interactive atmosphere of the meeting.

As judged from the experience of the organisers, there were many informal discussions between participants, which have and will lead to new collaborative work and interactions between labs which have not interacted before. This in turn will lead to more rapid and interesting progress in this fast moving field.

Programme
Thursday 30th June
Chromatin and Gene Expression - Sponsored by The Genetics Society
Session Chair: Jean Thomas
14.00 Introduction
14.10 Tony Kouzarides
Proline isomerisation of histone H3 regulates gene expression
14.35 Bryan Turner
Searching for an epigenetic code; beautiful ideas and ugly facts
15.00 Yang Shi
Posttranslational modifications of histone N-terminal tails impact chromatin structure and gene transcription
15.25 Genevieve Almouzni
Dynamic establishment of chromatin domains
15.50 Coffee
16.20 Renato Paro
The epigenetics of tissue regeneration in Drosophila
16.45 Robert Feil
The involvement of histone methylation in placenta-specific imprinting
17.10 Vicky Chandler
Heritable chromatin structures are established through trans-interactions between tandem repeats
17.35 Stephen Henikoff
Epigenetic patterns generated by assembly of histone variants into nucleosomes
18.00 Close

Thursday evening 30th June - Poster Session, Babraham Institute
Drinks will be served from 18.00 hours in the marquee during the poster session followed by dinner at 19.30 hours.

Friday 1st July
Stem cells, germ cells and plasticity
Session Chair: Jörn Walter
09.00 John Gurdon
Nuclear reprogramming in Xenopus
10.00 Rudolf Jaenisch
Nuclear cloning, stem cells and reprogramming of the genome
10.25 Austin Smith
Programming self-renewal
10.50 Coffee
11.20 Azim Surani
Epigenetic mechanisms of mouse germ cell specification and programming
11.45 Hiro Sasaki
Role of de novo DNA methyltransferases in male and female gametogenesis and genomic imprinting
12.10 Caroline Dean
Epigenetic regulation of the Arabidopsis floral repressor, FLC
12.35 Maria-Elena Torres-Padilla
Transcription in the life of an embryo, how does the mouse activate its genome?
12.50 Lunch
Higher order chromatin and chromosome dynamics
Session Chair: Adam West
14.00 Peter Cook
A model for all genomes, and the regulation of gene expression
14.25 Anne Corcoran
Antisense intergenic transcription: a processive role in ordered V(D)J recombination
14.50 Neil Brockdorff
Global Hypomethylation of the Genome in XX ES cells
15.15 Phil Avner
Imprinted X-inactivation:epimutation and epigenetic plasticity in trophoblast stem cells
15.40 Coffee
16.10 Denise Barlow
Non-coding RNAs silence imprinted genes
16.35 Cameron Osborne
Nuclear organization of transcription and a putative role in chromosomal translocations
16.50 Chiara Lanzuolo
A role for PREs in 3-D structure of the Drosophila Bithorax complex
17.05 Robert Fischer
Regulation of gene imprinting in Arabidopsis
17.30 Ueli Grossniklaus
Genomic impriting and PcG-mediated regulation during Arabidopsis seed development
17.55 Close

Friday evening 1st July - Babraham Institute
The evening, weather permitting will begin at 18.30 hours with drinks and canapés in the Walled Garden; this will be followed by a three course dinner served in the marquee.

Saturday 2nd July
DNA dynamics and repair
Session Chair: Peter Fraser
09.00 Alain Verreault
Histone H3 lysine 56 acetylation and the response to DNA strand breaks
09.25 Patrick Varga-Weisz
ATP-dependent nucleosome remodelling factors: Motors for epigenetic inheritance?
09.50 Svend Petterson-Mahrt
AID deaminates 5-methylcytosine in DNA and is implied in epigenetic reprogramming
10.15 Primo Schaer
Thymine DNA glycosylase regulates gene expression patterns
10.40 Coffee
11.10 Thomas Lindahl
Mechanisms of repair of deaminated and methylated DNA bases
Special Abstract Session
11.35 Heidi Sutherland
Is nuclear localisation important for repression of genes by KRAB zinc finger proteins?
11.50 Assen Roguev
Comparative proteomic mapping of chromatin related complexes in two yeasts
12.05 Susumu Uchiayma
Proteome analysis of human metaphase chromosomes
12.20 Arturo Gutierrez-Triana
Evolution of proteins related to DNA methylation in nematodes
12.35 Chandrasekhar Kanduri
Antisense transcription: A crucial component in the bidirectional silencing mediated by the mouse KCNQ1 imprinting control region
12.50 Lunch
Imprinting and development
Session Chair: Rebecca Oakey (Imprinting and Development)
14.00 Anne Ferguson-Smith
Developmental roles and regulation of Dlk1 in mouse development
14.25 Lawrence Wilkinson
Epigenetic mechanisms in behaviour
14.50 Rod Scott
Imprinting in flowering plants and mammals - what a comparison reveals
15.15 Gavin Kelsey
Imprinted genes and conflicts in their function and regulation
15.40 Coffee
Epigenomics and disease
Session Chair: Wolf Reik (Epigenomics and Disease)
16.10 David Bonthron
Insights into epigenetics from human genetic pathology - GNAS as an exemplar
16.35 Andy Mungall
Sequence Analysis of Vertebrate Orthologous Imprinted Regions (SAVOIR)
16.50 Daniel Mertens
Allelic silencing at the tumour suppressor locus 13q14.3 suggests a novel epigenetic mechanism
17.05 Dirk Schubeler
Genome-wide and promoter-specific analyses reveal sites of differential DNA methylation in normal and transformed human cells
17.30 Rob Martiensson
Making sense of heterochromatic RNA in plants and fission yeast.
17.55 Close

Saturday Evening 2nd July - Chilford Hall
The banquet dinner will be held at Chilford Hall, Linton. The evening began with drinks being served at 19.30 hours followed by the dinner served in the Pavilion and there was the opportunity to dance the night away to the sound of Awesome