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Gene Expression Unit Functional genomics of complex traits Previous and current research Individuals differ at thousands of DNA sequence positions. These differences interact with each other and with the environment in complex ways to give rise to heritable phenotypic variation. This is the basis of quantitative phenotypes such as body height, cancer, diabetes, crop yield and fungal virulence. Naturally occurring genetic variants also influence the onset and intensity of diseases, as well as their treatment susceptibility, thus providing an incentive for personalised medicine. The overall aim of our research is to elucidate how genetic variation conditions complex phenotypes. To this end, we integrate experimental and computational biology approaches at multiple layers along the molecular processes linking genotype to phenotype. In particular we investigate the level of the genome, transcriptome and proteome. Some selected projects include genotyping single-nucleotide polymorphisms across entire yeast genomes to infer meiotic recombination-activity distributions that define trait inheritance; studying the function of pervasive transcription of non-coding RNAs and the mechanisms of how they are generated; and analysing protein-interaction networks to enable the prediction of candidate disease genes for mitochondrial disorders. Future projects and goals We are developing new technologies to determine the phenotypic contribution for all sequence variants between two genomes in a single step. In addition, we are dissecting the genetic basis of sensitivity and resistance to malaria parasites in the mosquito, Anopheles gambiae. Ultimately, by integrating genetics, genomics, systems biology and computational modelling with high-throughput sequencing and microarrays, we aim to develop approaches that will enable personalised and preventative medicine across the world. The group is associated with the Stanford Genome Technology Center at Stanford University. Lars Steinmetz PhD 2001, Stanford University. Postdoctoral research at the Stanford Genome Technology Center. Group leader at EMBL since 2003. Academic Mentor, predoctoral training since 2008. Joint Unit Coordinator since 2009. Figure 1: High-resolution map of meiotic recombination inferred from genotype calls for all four spores of a single meiosis (Mancera et al., Nature, 2008) Figure 3 (right): From yeast proteininteraction datasets to the identification of candidate genes for human diseases (Perocchi et al., Mol. Biosyst., 2008) Figure 2: Bidirectional promoters generate pervasive transcription of non-coding RNAs (Xu et al., Nature 2009) Selected references Neil, H., Malabat, C., d’Aubenton-Carafa, Y., Xu, Z., Steinmetz, L.M. & Jacquier, A. (2009). Widespread bidirectional promoters are the major source of cryptic transcripts in yeast. Nature, 57, 1038-2 Xu, Z., Wei, W., Gagneur, J., Perocchi, F., Clauder-Munster, S., Camblong, J., Guffanti, E., Stutz, F., Huber, W. & Steinmetz, L.M. (2009). Bidirectional promoters generate pervasive transcription in yeast. Nature, 57, 1033-7 Mancera, E., Bourgon, R., Brozzi, A., Huber, W. & Steinmetz, L.M. (2008). High-resolution mapping of meiotic crossovers and noncrossovers in yeast. Nature, 5, 79-85 Sinha, H., David, L., Pascon, R.C., Clauder-Munster, S., Krishnakumar, S., Nguyen, M. et al. (2008). Sequential elimination of major-effect contributors identifies additional quantitative trait loci conditioning high-temperature growth in yeast. Genetics, 180, 1661- 1670 33
EMBL Research at a Glance 2009 Mechanisms of transcription regulation through chromatin Asifa Akhtar PhD 1998, Imperial Cancer Research Fund, London. Postdoctoral research at EMBL and Adolf-Butenandt- Institut, Munich. Group leader at EMBL since 2001. Previous and current research DNA tightly packed together with histones into nucleosomes is not easily accessible to the enzymes that use it as a template for transcription or replication. Consequently, remodelling of chromatin structure may play an essential role in the regulation of gene expression. Structural changes in chromatin may also form the basis for dosage compensation mechanisms that have evolved to equalise levels of X-linked gene products between males and females. In humans, one of the two X chromosomes in females is randomly inactivated by condensation of the chromosome into a Barr body, a process known as X-inactivation. In contrast, in Drosophila this is achieved by a two fold hyper-transcription of the genes on the male X chromosome. Genetic studies have identified a number of factors that are important for dosage compensation in Drosophila, including five proteins (MSL1, MSL2, MSL3, MLE, MOF) and two non-coding RNAs (roX1 and roX2). The hyperactive X is also specifically hyper-acetylated at histone H4, acetylation which is achieved by the MOF histone acetyl transferase. Our major goal is to study the epigenetic mechanisms underlying X-chromosome specific gene regulation using Drosophila dosage compensation as a model system. More specifically, we are interested in addressing how the dosage compensation complex, composed of RNA and proteins (the MSL complex), gets targeted to the X chromosome. In addition, we are studying the mechanism by which the MSL complex modulates X chromosomal transcriptional output. Future projects and goals The role of nuclear periphery in X chromosomal regulation. We have recently discovered the involvement of nuclear pore components in the regulation of dosage compensation in Drosophila. This work has raised several interesting questions about the role of genome organisation and gene regulation, which we will continue to actively address in the future. In addition to using functional genomic approaches, we plan to study in detail the mechanism of nuclear pore/X chromosomal interaction by employing detail cell biology and biochemical chromatin-based strategies. This multifaceted approach will be instrumental in future studies to decipher the mechanism of X chromosomal regulation by the MSL complex. Immunostaining of polytene chromosomes from salivary glands of male Drosophila using antibodies directed against members of the dosage compensation complex (DCC). The figure shows that MSL-3 and MSL-2 co-localise specifically on hundreds of sites on the male X chromosome. All the chromosomes are also stained with Hoechst to show staining of DNA. The position of the X chromosome is indicated by X. The role of non-coding RNA in dosage compensation. The involvement of non-coding RNAs as potential targeting molecules adds another level of complexity to chromatin regulation. Interestingly, the dosage compensation complex includes two non-coding roX RNAs. However, the mechanism by which these RNAs function is unknown. One of our future aims will be to elucidate how these interactions influence transcription activation of the X-linked genes. The function of the mammalian MSL complex. There is a remarkable evolutionary conservation of all the known Drosophila dosage compensation complex members in mammals. In fact, we have recently purified the Drosophila and mammalian MSL complexes and shown that there is a high degree of conservation also at the biochemical level, implying a functional role for the mammalian MSL complex in gene regulation which we will continue to study. Selected references Kind, J., Vaquerizas, J.M., Gebhardt, P., Gentzel, M., Luscombe, N.M., Bertone, P. & Akhtar, A. (2008). Genome-wide analysis reveals MOF as a key regulator of dosage compensation and gene expression in Drosophila. Cell, 133, 813-828 Kind, J. & Akhtar, A. (2007). Cotranscriptional recruitment of the dosage compensation complex to X-linked target genes. Genes Dev., 21, 2030-200 Legube, G., McWeeney, S.K., Lercher, M.J. & Akhtar, A. (2006). X- chromosome-wide profiling of MSL-1 distribution and dosage compensation in Drosophila. Genes Dev., 20, 871-883 Mendjan, S., Taipale, M., Kind, J., Holz, H., Gebhardt, P., Schelder, M., Vermeulen, M., Buscaino, A., Duncan, K., Mueller, J., Wilm, M., Stunnenberg, H.G., Saumweber, H. & Akhtar, A. (2006). Nuclear pore components are involved in the transcriptional regulation of dosage compensation in Drosophila. Mol. Cell, 21, 811-823 3
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