All tags Epigenetics Chromatin: from nucleosomes to chromosomes

Chromatin: from nucleosomes to chromosomes

Meeting report on Chromatin: from nucleosomes to chromosomes conference, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK, 30 April - 2 May 2014.

By Michael Schubert

Graduate Assistant, Grigoryev Lab, Pennsylvania State University, College of Medicine, Dept. of Biochemistry and Molecular Biology.

Presenters from across Europe and North America came together at the Wellcome Trust’s recent conference to discuss advances and techniques in the study of chromatin structure and function. 

While the meeting was smaller than usual due to relocation during the construction of the new Wellcome Trust Conference Centre, it featured an impressive roster of delegates with a wide range of research topics. 

There was significant focus on variant histone proteins in particular, as well as interest in chromatin domains and the structure and dynamics of chromatin in living cells.   

Two keynote speakers – Jane Mellor from the University of Oxford and William C. Earnshaw from the University of Edinburgh – shared insights gained from careers spent studying epigenetics and chromatin. 

Dr. Mellor opened the conference by speaking on histone modification and the yeast metabolic cycle, linking the effects of acetylation, methylation and directional RNA transcription on various regulatory genes. 

Dr. Earnshaw traced the understanding of structure in the nucleolus and the mitotic chromosome from early studies on centromeric proteins to modern-day proteomics and systems for the study of conditional protein degradation.

Nucleosome positioning and remodeling

During the first conference session, speakers addressed the widespread effects of chromatin-remodeling proteins and contributors to chromatin conformation. Adam Buckle presented recent findings on the regulatory organization of the PAX6 locus, including the role played by architectural proteins.

Alea Mills and David Clynes spoke about the chromatin remodelers Chd5 and ATRX respectively, showing the proteins' effects on neuronal cell fate and genomic stability.

In addition, both speakers discussed the implications of their findings in cancers of the nervous system, knowing that Chd5 is deleted in human gliomas and many other cancers, whereas ATRX is mutated in gliomas and other brain tumors that make use of an alternative telomere lengthening pathway.

Histone variants and chaperones

This session was opened by Sandra Hake who identified a gap in understanding whereby the biological functions and mechanisms of the histone variant H2A.Z are well-known, but its cellular role is much less understood. 

Showing that the different H2A.Z proteins form different complexes including novel proteins associating with each, Dr. Hake was able to shed light on some of the potential functions of this histone variant in the cell. 

Emily Bernstein discussed a new role for H2A.Z isoforms in the context of melanoma progression, as well as discussing the role of macroH2A in transcriptional repression and prevention of melanoma metastasis. 

Simon  Elsässer then presented on a new deposition pathway for histone variant H3.3 involved in heterochromatin maintenance and genome stability in mouse embryonic stem cells.

Histone modifications and chromatin states

Topics in this session ranged widely, from chromatin state maps to the functions of various proteins in remodeling.

Julie Ahringer spoke on the mapping of chromatin in the C. elegans genome, describing the boundary states of gaps between active and inactive gene blocks, while A. Francis Stewart talked about the differing behaviors of methyltransferases during mouse embryonic development, showing that different histone 3 lysine 4 methyltransferases are required at different points in development and that their absences yield different phenotypes. 

Stewart went on to propose that  histone 3 lysine 4 methylation is a multiply-backed-up, but imperfect, system.  Finally, Peter Verrijzer gave a talk on the role of CAF1 and ISWI in protamine deposition and genome repackaging in the male germline.

Gene regulatory control

Eileen E.M. Furlong opened this session with an exciting talk on enhancer-promoter interactions and their proximity during embryogenesis, showing many more physical interactions than were previously known and revealing new information about the dynamics of enhancer behaviors during development. 

Her talk was followed by Jim R. Hughes, who described a new, scalable high-throughput technique for analyzing chromatin conformation, and  Gernot Längst, who discussed techniques for examining nucleosome accessibility and sensitivity in vivo, as well as the effect of TNFα on nucleosome repositioning and chromatin accessibility to NF-κB

To round out the session, Adam G. West presented on the transcription factor VEZF1 and its key role in gene regulation.

DNA methylation and gene silencing

This session began with a talk by M. Cristina Cardoso on relating DNA replication studies and three-dimensional cell imaging to elucidate the spatio-temporal organization of DNA replication and repair. 

Connections between replicons, repair nano-foci and chromosome higher-order structure were described, suggesting a model for replication in mammalian cells that corresponds to observed dynamics. 

Mathieu Boulard then presented evidence revealing that CpG islands are actively protected against de novo methylation. 

He was followed by Dirk Schübeler on the subject of locus-specific targeting of different DNA methyltransferases, showing a link between underlying sequence features, protein binding and ultimately methylation.

Polycomb-mediated regulation

To introduce the topic of Polycomb group complexes, Rob Klose spoke about the relationship between CpG islands and Polycomb group proteins, proposing a novel recruitment pathway for Polycomb repressive complexes. 

Ajaz ul H Wani continued by discussing the role of polyhomeotic polymerisation in the regulation of nuclear organization and chromatin topology of Polycomb group proteins. 

Adrian P. Bracken finished the session by focusing on Polycomb-like proteins and their divergent roles in cell cycle control, emphasizing not only their functions as part of the PRC2 complex, but also as independent proteins with distinct effects.

Chromatin fiber conformation and dynamics

The first speaker of two sessions focusing heavily on chromatin structure was Kazuhiro Maeshima, who showed that chromatin essentially consists of irregularly folded nucleosome fibers without the 30 nm chromatin structure in the cells. He also demonstrated a large nucleosome fluctuation in live mammalian cells by single nucleosome imaging.

Artur Kaczmarczyk presented single-molecule analysis of chromatin fibers through magnetic tweezer experiments, showing the chirality of the fibre helix and the effect of supercoiling on its unfolding, while Michael Schubert tackled the heteromorphicity of the fiber and offered a structural hypothesis for its absence in the mitotic cell. 

Nick Gilbert maintained interest in supercoiling, discussing patterns of DNA winding at CpG and non-CpG island promoters and their ultimate effect on gene activation.

Edith Heard started the second session with a talk on the relationship between chromosome structure and function in X-inactivation, sharing results on chromosome folding into topologically-associated domains and exploring the functional relevance of these domains by combining physical modeling of 5C data with high resolution FISH and genetic testing of functional predictions of the model. 

Other speakers included Peter D. Adams, who presented research on the role of  histone chaperone HIRA in cellular senescence and tumor suppression via control of the chromatin landscape, and Daniel Ricketts, who expanded on this work by exploring the role of ubinuclein-1 on the HIRA complex and its ability to bind and deposit histone variant H3.3

Christian Speck also spoke, outlining the relationship between the structure of replicative helicase Mcm2-7 and its loading and activation mechanisms at replication origins.

Chromosome integrity

In the final session of the conference, topics ranging from DNA methylation to histone modifications to chromatin structure were discussed, touching upon many key areas of interest in current chromatin science. 

William A. Pastor gave an overview of the Morc1 protein and its novel function in DNA methylation during embryonic germ cell development, providing a potential link between chromatin compaction and gene regulation. 

Laia Sadeghi discussed the role of histone H2B mono-ubiquitination in the maintenance of euchromatin and centromere stability, while Ben Black continued the centromeric theme with a talk on the chromatin structure foundation of the centromere and the contribution of the CENP-A nucleosome to its recognition and propagation throughout the cell cycle. 

To conclude the conference, Luis Aragon gave a detailed presentation on the catenation of sister chromatids during yeast mitosis and the function of topoisomerase II and strand proximity in removing and further regulating those catenanes.

Speakers at the “Chromatin: From nucleosomes to chromosomes” conference were uniformly excellent, and the poster sessions equally showed the breadth of research interests and quality of the delegates. 

At all levels from basic biophysics to translational medicine, research being conducted in the varied fields of chromatin structure and function promises to be both exciting and relevant for a long time to come.

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