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Developmental Biology Unit Gene regulation and genome architecture in development and evolution Previous and current research Embryonic development is organised by a large number of genes, for which expression levels and specificities have to be tightly regulated at the transcriptional level. In vertebrates, this is achieved with genes being regulated by batteries of cis-elements, which act in modular, synergetic and complementary manners. These regulatory elements are often found spread over large chromosomal domains that contain multiple genes with distinct functions and expression profiles, an intricate situation most probably due to regulatory tinkering during evolution. Several functional and computational approaches have been successful in predicting or identifying cis-regulatory elements for a number of genes. However, and in contrast, the molecular mechanisms that translate the intermingled arrays of gene and cis-regulatory elements – which compose vertebrate chromosomes into coherent gene-specific expression programmes – are poorly understood. The dramatic consequences of several chromosomal rearrangements found in humans illustrate that, besides the mere presence of cis-regulatory elements, the specific structure of a locus may contribute substantially to gene expression, underscoring the existence and importance of the genome regulatory architecture. More generally, the changes in this architecture associated with the widespread structural variations recently described in humans may also modulate the expression profile of the surrounding genes, leading to increased phenotypic diversity. However, in both cases, the molecular and regulatory mechanisms associated with this dimension of the genome are mostly unknown. Our work aims to explore the nature of the vertebrate regulatory genome and identify the underlying mechanisms. As model systems, we focus on few megabase-large genomic loci, which organisation is extensively conserved within vertebrates, or where rearrangements have been associated with developmental genetic abnormalities in humans. We are using mouse transgenesis to identify the regulatory elements that control the specific activities of the multiple genes present in these loci, and state-of-the-art chromosomal engineering techniques to create series of mouse lines with deletions, duplications and inversions to reshuffle these loci in various ways, some replicating known human genetic disorders. By combining these approaches, we are starting to unravel the intricate regulatory organisation of these regions, as well as to get insights into the mechanisms that control and restrict the functional interactions between cis-regulatory elements and neighbouring genes. Future projects and goals X-rays of mouse limb malformations associated with changes in genome regulatory architecture in cis or in trans. François Spitz PhD 1997, Institut Cochin de Génétique Moléculaire, Paris. Postdoctoral research at the University of Geneva. Group leader at EMBL since 2006. We aim to develop our understanding of functional and regulatory organisation of the mammalian genome, using genetic and chromosomal re-engineering approaches in mice as well as functional and computational genomics. In particular, if it is known that changes in chromatin structure, conformation and localisation within the nucleus are associated with different transcriptional activities, the hierarchy of these events and how they are determined by the genomic sequences are still poorly understood. The mouse lines we have generated, with differentially rearranged chromosomal domains, allow us to investigate the relationships between genome sequence, chromatin structure and gene expression by combining phenotypic and gene expression assays with chromatin profiling, conformation analysis and imaging. We have recently developed efficient transposition and recombination strategies, enabling rapid generation of transgene insertions and chromosomal rearrangements in vivo. We aim to use these tools to further chart the regulatory architecture of the mammalian genome, and also to investigate the molecular and phenotypic consequences of structural variations found in humans. We are also interested in comparing regulatory architecture between different species, to trace back its emergence during evolution and the associated evolutionary regulatory tinkering. We are particularly interested by the role of ancestral mobile elements, which appear to have been exapted into yet-to-be-determined functions (project funded by HFSP, in collaboration with Gill Bejerano, Stanford). Selected references Friedli, M., Nikolaev, S., Lyle, R., Arcangeli, M., Duboule, D., Spitz, F. & Antonarakis, S.E. (2008). Characterization of mouse Dactylaplasia mutations: a model for human ectrodactyly SHFM3. Mamm. Genome, 19, 272-278 Spitz, F. & Duboule, D. (2008). Global control regions and regulatory landscapes in vertebrate development and evolution. Adv. Genet., 61, 175-205 Gonzalez, F., Duboule, D. & Spitz, F. (2007). Transgenic analysis of Hoxd gene regulation during digit development. Dev. Biol., 306, 87- 859 Spitz, F., Herkenne, C., Morris, M.A. & Duboule, D. (2005). Inversioninduced disruption of the Hoxd cluster leads to the partition of regulatory landscapes. Nat. Genet., 37, 889-893 29
EMBL Research at a Glance 2009 Mathias Treier PhD 199, University of Heidelberg. Postdoctoral research at the University of California, San Diego. Group leader at EMBL since 2000. Joint appointment with EMBL Monterotondo. Mammalian organogenesis and physiology Previous and current research The specification of cell types during organ development has been studied intensively over the last decade. The future challenge is to understand how these different cell types function in a concerted action within an organ to fulfill its physiological task, and ultimately how mammalian physiology is orchestrated to allow an organism to survive. We employ mouse genetics to study various aspects of mammalian physiology, from the single cell stage to the complex interplay between organs that allow an organism to maintain energy homeostasis. Stem/progenitor cell populations constitute the basic building units from which organs and whole organisms are created. We have identified with the transcriptional regulator, Sall4, one of the key players that is required to maintain the pluripotency state of embryonic stem cells. Sall4 is highly expressed in the inner cell mass (ICM) of a blastocyst which will give rise to the embryo proper and the primitive endoderm. We could demonstrate that Sall4 is essential for self-renewal of embryonic stem cells as well as progenitor cells of the primitive endoderm derived from the ICM. We are currently employing genetic and biochemical methods to understand the regulation and function of this important player in stem cell biology in greater detail. At the organ level our research is mainly focussed on the kidney. We are interested in both the development of the organ as well as the physiological functions the kidney has to perform to maintain homeostasis at the organismal level. Many life-threatening inherited genetic disorders manifest themselves as malfunctions of the kidney, a particular example being polycystic kidney disease (PKD), which affects an estimated 13 million people worldwide regardless of sex, age, race or ethnic origins (www.pkdcure.org). Whereas PKD leads to an enlargement of the organ through uncontrolled growth, another debilitating kidney syndrome is nephronophthisis, in which the kidneys shrink. Both syndromes are believed to result from aberrant signalling of an ancient organelle present on most kidney cells called the cilium, the sensor that allows kidney cells to react to changes in physiological parameters within the blood and urine (see figure). With the Glis family of transcriptional regulators, we have identified molecular players that are involved in transmitting the signal from the cilium to the nucleus, allowing kidney cells to respond to changes in their environment. We are now investigating at the molecular level how signal transmission is regulated through post-translational modifications. Understanding cilia signalling in general will have implications for many other human diseases, like for example Bardet-Biedel syndrome, that are caused by malfunctioning of this organelle. The ultimate challenge in systems biology is to understand mammalian physiology. For any living organism, maintaining energy homeostasis is the central task for survival. We are particular interested in the neuronal circuits in the central nervous system (CNS) that are regulating energy balance. We have identified the brain-specific homeobox protein Bsx as an essential player in the regulation of food intake and locomotor activity, the two main components that determine energy homeostasis. We are currently investigating how higher brain centres interact with peripheral signals that signal satiety and hunger to regulate our drive to eat. In light of the obesity pandemic resulting in metabolic syndrome with its complications like type 2 diabetes, the understanding of the molecular mechanisms maintaining energy homeostasis has gained one of the highest priorities. Future projects and goals Transcriptional regulators will continue to be central to our investigation. Many can directly sense environmental cues and as a consequence alter the transcriptional readout from our individual genetic blueprint. With a series of mouse models for human diseases that we have created over the years, we are Schematic drawing of a cilium transmitting an extra-cellular signal to the nucleus. now in a position to dissect even complicated physiological questions at the organismal level. In parallel, we have started to look at how metabolism influences degenerative processes to open new avenues for pharmacological treatments in regenerative medicine. Selected references Uhlenhaut, N.H. & Treier, M. (2008). Transcriptional regulators in kidney disease: gatekeepers of renal homeostasis. Trends Genet., 2, 361-371 Attanasio, M., Uhlenhaut, N.H., Sousa, V.H., O’Toole, J.F., Otto, E., Anlag, K., Klugmann, C. et al. (2007). Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nat. Genet., 39, 1018-102 Sakkou, M., Wiedmer, P., Anlag, K., Hamm, A., Seuntjens, E., Ettwiller, L., Tschop, M.H. & Treier, M. (2007). A role for brainspecific homeobox factor bsx in the control of hyperphagia and locomotory behavior. Cell Metab., 5, 50-63 Elling, U., Klasen, C., Eisenberger, T., Anlag, K. & Treier, M. (2006). Murine inner cell mass-derived lineages depend on Sall function. Proc. Natl. Acad. Sci. USA, 103, 16319-1632 30
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