The EMBL Advanced Training Centre auditorium was near full capacity during the 11th EMBL Transcription and Chromatin conference, from 23 to 26 August 2014 at EMBL Heidelberg, with barely an empty seat in sight.
By Ina Hollerer
The EMBL Advanced Training Centre auditorium was near full capacity during the 11th EMBL Transcription and Chromatin conference, from 23 to 26 August 2014 at EMBL Heidelberg, with barely an empty seat in sight. As EMBL’s longest running conference, “this year’s event lived up to its important role in the transcription field over the past 20 years”, said organiser Eileen Furlong, Head of the Genome Biology Unit at EMBL Heidelberg, pointing out the mix of leading experts and interested students and scientists from all over the world who were drawn to the event to discuss cutting edge research.
a great platform to exchange ideas
“This conference has always been a grand opportunity to meet and discuss with colleagues in and outside the field,” pointed out Geneviève Almouzni, invited speaker and director of the Institut Curie. “It provides a great platform to exchange ideas in a scientific environment,” she added, echoing feelings voiced by many throughout the meeting.The conference featured a variety of interesting talks and posters covering different aspects of transcription, and promoted interactive discussion about the latest breakthroughs in the field.
Large-scale meets basic biochemistry
The meeting outlined exciting progress in the development of advanced techniques needed to study transcription regulation on a global scale, while simultaneously demonstrating the importance of basic biochemistry when studying biological mechanisms in detail. “In my opinion, we need both: state-of-the-art high-throughput technologies, and basic biochemistry tools, to bring all the bits and pieces together and understand transcription in all its complexity,” remarked co-organiser Marc Timmers.
this interdisciplinarity makes it a really exciting area to work in, and you can feel that excitement at conferences like this
Furlong presented one example of the successful application of global techniques to study the regulation of transcription. Chromosome Conformation Capture Sequencing (4C-seq), a method to study DNA contacts made across the genome, enabled researchers in the Furlong lab to look at 100 enhancers that are active during embryonic development in Drosophila and map what DNA elements – genes, promoters and other enhancers – they establish contacts with, in 3D. This revealed that, as well as interacting with nearby elements as expected, Drosophila enhancers also establish numerous long-range interactions. And each enhancer contacts several enhancers and promoters, suggesting that these elements could be jointly regulated. Surprisingly, those interactions seem to be similar in different tissues, and to remain largely largely unaltered at least during the two stages of development examined. And as Furlong pointed out, the remarkable degree of complexity this approach uncovered indicates a close similarity between flies and humans.
Also turning to the topic of enhancers, Ali Shilatifard from the Stowers Institute for Medical Research summarised data on the role of single proteins in enhancer-promoter communication and discussed recent findings in the identification of enhancer mutations linked to cancer. He was just one of the numerous speakers who underlined the importance of gaining a detailed understanding of the cellular mechanisms that contribute to transcription regulation. Almouzni noted: ”Exploring the basics, that is, single players influencing transcription regulation, contributes to helping to understand fundamental principles.”
Hot topic: epigenetics
The conference gave a taste of where the field of transcription is heading and a glimpse of the future potential of several research topics, but to Almouzni, one clearly stood out. “The relation between epigenetics and disease is clearly a hot topic,” she said. “We have learned a lot from genetic mutations being the driver of certain diseases. But in the future we’ll need to consider the epigenetic landscape to a greater extent.” Epigenetics refers to any heritable changes that are not the result of alterations to the DNA sequence, including the various chemical tags that serve as landmarks for the cell’s transcription machinery, regulating which parts of a cell’s DNA are read when. Almouzni’s own work has contributed to the current understanding of a key aspect of that landscape: the dynamics of chromatin and how it is regulated in response to external stimuli. Almouzni presented recent results from her lab, which revealed that specific chaperones deposit different types of histone onto the DNA, creating a histone landscape which influences the overall epigenome, contributing to a cell’s unique transcriptional profile.
Histones, their interaction with chromatin, and the nucleosomes formed by these two structures were the subject of several other talks, too. Some labs focus on mapping histone marks and their changes in response to different stimuli, like the lab of Ann Ehrenhofer-Murray at Humboldt-University Berlin. This group found a new post-transcriptional modification – a chemical tag that influences how the transcription machinery acts – which regulates gene activation in the yeast S. cerevisiae. Others are investigating the general impact of nucleosome deposition on transcription: Steven Henikoff from the Fred Hutchinson Cancer Research Center showed that nucleosomes are barriers to transcription in vivo. Henikoff presented evidence that transcription-generated torsion dismantles nucleosomes, allowing RNA polymerase to access – and transcribe – the DNA in those otherwise inaccessible regions.
Several other research groups presented interesting findings on how epigenetics influence phenotypes, contributing to developmental defects and disease. Laurie Boyer and her team from MIT found that many of the single-letter mutations detected in Genome-Wide Association Studies (GWAS) – where whole genomes of people with and without a certain condition are compared, in an attempt to identify mutations that are linked to that condition – occur not in genes but rather in enhancer regions, influencing the expression of disease-related genes, something that has been observed in other contexts. In addition to these single letter mutations, larger genome rearrangements can have disastrous effects on enhancer activity. Francois Spitz from EMBL Heidelberg showed how chromatin boundaries, generated by so called topological domains, act to limit enhancer activity and altering these leads to developmental phenotypes. This exciting result fits with data presented by Denis Duboule from the École Polytechnique Fédérale de Lausanne, showing that enhancer contacts can be expanded depending on the tissue a cell belongs to.
The chicken or the egg?
One of the recurring questions transcription researchers grapple with is ‘What is driving what?’ “Does transcription regulate chromatin organisation? Is chromatin remodeled before transcription begins? Or do both happen simultaneously?,” Furlong pondered. “We don’t yet know exactly how chromatin assembly and transcription are linked time-wise, especially during embryonic development.” Many research groups are working on answering this question by resolving the structure of the essential transcription machinery. Among them are the Müller group at EMBL, and the Cramer laboratory from Ludwig Maximilian University (LMU) in Munich. Christoph Müller presented recent data on the structure of RNA polymerases I and III, and explored how these structures hint at the enzymes’ functions in transcription. Cramer discussed insights into the structural basis of transcription initiation. By combining different structural biology methods, such as X-ray crystallography and single-particle cryo-electron microscopy, Cramer and his team aim to elucidate how transcription initiation is regulated in a cell.
In general, the conference highlighted the importance of looking at transcription as an integrated complex process, which requires a combination of different focuses and techniques to unravel. As Furlong concluded: “To really have an overarching view of how transcription is regulated, we’ll need information from many different levels, which requires people from a variety of fields – this interdisciplinarity makes it a really exciting area to work in, and you can feel that excitement at conferences like this one.”
The 2014 meeting was organised by Eileen Furlong, Marc Timmers, Denis Duboule and Ali Shilatifard. The next meeting will be held on 27th-30th August 2016.