Nuclear architecture

GENEVIÈVE ALMOUZNI FR

Institut Curie, Paris

Shaping chromatin in the nucleus, the bricks and the architects
Chromatin organization in the nucleus provides a large repertoire of information in addition to that encoded genetically. A major goal for my group involves understanding how histones, the major protein components of chromatin, the bricks, can mark functional regions of the genome through their variants or post-translational modifications, along with non-coding RNA and other chromatin regulators. Errors in the establishment and propagation of these chromatin components, possibly involving imbalance in their deposition pathways, can lead to mis-regulation of genome functions and pathological outcomes, such as cancer. The propagation of centromeric identity represents a model of choice for the study of epigenetic mechanisms. Our work has focused on histone chaperones, as architects of chromatin organisation. We will present our latest findings.

Biography
Geneviève Almouzni, PhD, is chair of the Unit "Nuclear dynamics" UMR3664 CNRS/Institut Curie, in Paris, France. She obtained her PhD in 1988 from the University Pierre and Marie Curie, Paris. She carried out her postdoctoral research at NIH, Bethesda, USA and contributed to the characterization of the importance of chromatin for transcriptional regulation. In 1994, she was appointed as a junior group leader at the Institut Curie to develop her independent research on chromatin dynamics. Her work contributed to many aspects of chromatin analysis from the development of in vitro systems, to the identification of the role of key histone chaperones. Her current interest is to understand the basic principles underlying the 3D organization of the cell nucleus and their interrelationships with genome stability, in the context of development and cell cycle, in normal and pathological situations. She received prestigious awards and was elected at the Académie des Sciences in 2013. She received the FEBS/EMBO Women in Science award and the AAAS award the same year. In 2014, she also was nominated vice-chair of the EMBO council. Since September 2013, she was appointed director of the Research Center at the Institut Curie.

WENDY BICKMORE UK

MRC Human Genetics Unit, University of Edinburgh

Linking three-dimensional genome organization to function

Human genome function cannot be understood by only considering linear DNA sequence. Several aspects of spatial genome organization – including localization at the nuclear periphery and the folding of chromosome domains - are linked to the regulation of gene expression. Long-range enhancers, located as much as 1 megabase from their target gene, are key in controlling the correct spatial and temporal expression of genes and three-dimensional chromatin folding must play a fundamental role in this enhancer-promoter communication. I will describe our work to investigate the three-dimensional folding of the mammalian genome. I will show how different experimental approaches – molecular biology, high-resolution imaging and synthetic biology - can be combined to address this fascinating aspect of transcriptional control.

Biography

Wendy Bickmore is the director the MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine at the University of Edinburgh. She is fascinated by the structure and organization of chromosomes in the nucleus. She showed that different human chromosomes have preferred positions in the nucleus, related to their gene content, and addressed how genes are organized and packaged in the nucleus and how they move in the cell cycle and during development. Current research in Wendy Bickmore's laboratory focuses on how the spatial organization of the nucleus influences genome function in development and disease. Wendy is an EMBO member, a Fellow of the Royal Society of Edinburgh and of the Academy of Medical Sciences and is the new president of the UK Genetics Society. She is an editor on many journals including PLoS Genetics and Cell.

SUSAN M. GASSER CH

Friedrich Miescher Institute for Biomedical Research, Basel

Histone H3K9 methylation: safeguarding repetitive genomes

Eukaryotic genomes contain millions of copies of repetitive elements (RE). It is estimated that between 50 and 70% of the human genome is composed of repeats, which include both small nucleotide stretches (tandem repeats) and transposable elements (RNA and DNA transposons). Repetitive elements are transcriptionally silenced by heterochromatin, of which the methylation of histone H3 at lysine 9 is a hallmark. The nematode C. elegans, has two histone methyltransferases responsible for H3K9 modification:  MET-2, which is the SetDB1 homologue, and SET-25, which has a SET domain similar to G9a.  Deletion of both leads to a total loss of H3K9methylation in the embryo and larval stages 1-3.  Worms lacking H3K9me show a striking increase in the transcription of all RE classes (DNA transposons, retrotransposons and tandem repeats) mainly in somatic tissues. By using ChIPseq and RNAseq to analyze the biology of worm RE’s, we identified elements that are silenced by H3K9me3 as opposed to mono- and di-methylation. Surprisingly, worms completely lacking H3K9me are viable, although they become sterile at 25°C.  Their sterility correlates with a dramatic increase in DNA-damage checkpoint dependent apoptosis during oogenesis and a strong increase in repeat expression. A genome wide synthetic lethality screen, demonstrated a strong dependency of worms lacking H3K9me on DNA damage response proteins for fertility. We could further show that H3K9me deficient mutants have a strong increase in spontaneous mutation rates, both when scored using a heterochromatic gene reporter, or as spontaneous genomic changes.  The lesions  include frameshifts, translocations, insertions and deletions. We observe no detectable increase in neither mitotic nor meiotic chromosome missegregation, arguing that the genomic instability is no due to a potential role of H3K9me in chromosome segregation.   We conclude that H3K9 methylation plays a unique and crucial role in the stabilization of repetitive DNA.

Biography

Prof. Susan M. Gasser is the director of the Friedrich Miescher Institute for Biomedical Research, a position she assumed in 2004. In parallel, she holds a professorship at the University of Basel. Before joining the FMI, Susan Gasser was Professor of Molecular Biology at the University of Geneva, and for the preceding 15 years, she led a research group at the Swiss Institute for Experimental Cancer Research in Epalinges/Lausanne, Switzerand. Susan Gasser's studies how nuclear organization impinges on mechanisms of repair and replication fork stability and on epigenetic inheritance of cell fate decisions. She exploits the genetics of model organisms in her studies, as well as quantitative live fluorescence imaging. She has authored more than 250 primary articles and reviews, and has received a number of awards for her work, including election to the Académie de France, to the Swiss Academy of Medical Sciences, FEBS | EMBO Women in Science Award 2012, the INSERM International Prize in 2011, and both the Otto Naegeli Award and the Gregor Mendel Medal in 2006. She is a member of the President's Science and Technology Advisory Council of the European Commission, and serves on scientific review panels for institutes across Europe.