ayout 1 - EMBL Grenoble

EMBL Research at a Glance 2009
Jürg Müller
PhD 1991, University of
Zürich.
Postdoctoral research at the
MRC Laboratory of Molecular
Biology, Cambridge.
Junior group leader at the
Max-Planck-Institute for
Developmental Biology,
Tübingen.
Group leader at EMBL since
2001.
Chromatin and transcription in development
Previous and current research
Our laboratory studies the biochemical mechanisms by which chromatin-modifying enzymes and
chromatin-binding proteins regulate gene transcription. In particular, our work is focussed on the
molecular mechanisms by which chromatin proteins encoded by the Polycomb group (PcG) and
the trithorax group (trxG) of genes stably and heritably maintain expression states of target genes.
PcG and trxG proteins are two evolutionary conserved sets of transcriptional regulators that control
a plethora of developmental processes in both animals and plants. PcG proteins act as repressors
that keep target genes inactive in cells where these genes should not be expressed, while
trithorax group proteins promote transcription of the same target genes in other cells. Although
the PcG/trxG system is best known for its role in maintaining spatially-restricted expression of developmental
regulator genes in animals and plants, it is also used for processes ranging from X-
chromosome inactivation in mammals to the control of flowering time in plants.
We study the PcG/trxG system in the model system Drosophila using an integrated approach that
combines a variety of biochemical, biophysical, genetic and genomic assays. One focus of our research
during recent years has been the biochemical purification of PcG protein complexes and
working out their molecular mechanisms. We thus found that PcG protein complexes contain enzymatic
activities that add or remove particular post-translational modifications at specific lysine
residues in histone proteins in chromatin, including a histone methyltransferase and a histone
deubiquitylase. Our analysis of PcG protein complexes also revealed that they contain subunits that
allow these complexes to bind to specific post-translational modifications such as methylated
lysines on histone proteins. From discovering these activities in vitro, we then proceeded to dissect how they regulate gene expression in vivo,
by studying where PcG and trxG protein complexes bind to target genes in Drosophila and how their enzymatic activities modify target gene
chromatin. By comparing the chromatin of target genes in wild-type and mutant Drosophila strains and by performing structure/function
analyses of PcG proteins in Drosophila, we have obtained critical insight into the mechanisms by which these chromatin-modifying and -binding
activities regulate gene transcription. For these studies we use a combination of detailed in-depth analyses at the single gene level and global
analyses at the level of the entire genome.
Future projects and goals
Our long-term goal is to understand how transcriptional ON and OFF states are controlled by the Polycomb/trithorax system and how they
are propagated through replication and cell division. The strength of our approach is the combination of Drosophila genetics and global
genome-wide analyses in vivo with detailed in-depth biophysical and biochemical analyses in vitro. Whilst we will continue to use these strategies
to study the Polycomb/trithorax system, we are moving on to study how chromatin-modifying and chromatin-binding proteins dynamically
interact with nucleosomes of defined modification states at the single molecule level. A second recent focus is the functional dissection
of the ‘histone code’ in Drosophila using genetic approaches.
Selected references
Oktaba, K, Gutierrez, L., Gagneur, J., Girardot, C., Sengupta, A.K.,
Furlong, E.E.M. & Müller, J. (2008). Dynamic regulation by Polycomb
group protein complexes controls pattern formation and the cell
cycle in Drosophila. Dev. Cell, 15, 877-889.
de Ayala Alonso, A.G., Gutierrez, L., Fritsch, C., Papp, B., Beuchle,
D. & Muller, J. (2007). A genetic screen identifies novel polycomb
group genes in Drosophila. Genetics, 176, 2099-2108
Nekrasov, M., Klymenko, T., Fraterman, S., Papp, B., Oktaba, K.,
Kocher, T., Cohen, A., Stunnenberg, H.G., Wilm, M. & Muller, J.
(2007). Pcl-PRC2 is needed to generate high levels of H3-K27
trimethylation at Polycomb target genes. EMBO J., 26, 078-088
Papp, B. & Muller, J. (2006). Histone trimethylation and the
maintenance of transcriptional ON and OFF states by trxG and PcG
proteins. Genes Dev., 20, 201-205
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