Chromatin structure and function

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 focused on the molecular mechanisms by which chromatin proteins encoded by the Polycomb group (PcG) and the trithorax group (trxG) of genes maintain transcriptional OFF and ON states of target genes.  PcG and trxG proteins are two evolutionary conserved sets of regulatory factors 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 genes that control body patterning 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 use the model system Drosophila to elucidate the basic principles of how the PcG/trxG system works. To this end, we use an integrated approach that combines biochemistry, structural biology, genetics and genomics.  Our past research established that PcG and trxG proteins are the subunits of multiprotein assemblies and we found that these protein complexes act as enzymes that alter chromatin by adding or removing post-translational modifications on histone proteins.  These modifications include the methylation and the monoubiquitylation of specific lysine residues in histone proteins that, through the use of histone genetics, we showed to be essential for regulation by the PcG/trxG system.  In addition, PcG proteins also modify chromatin structure through non-enzymatic activities that are also essential for gene regulation in vivo but, at the mechanistic level, are much less well understood. Our recent research has helped to understand how histone lysine methylation permits to maintain gene transcription states and how it works to propagate these states through replication and cell division.  Quantification of the complete nuclear proteome and of histone post-translational modifications in Drosophila has also given us the framework for understanding the stoichiometric relationships between PcG/trxG components and other protein factors in the cell.

Future projects and goals

A first area of our current research is to use structural biology to get an understanding of the architecture of these protein complexes and how they recognize nucleosomes.

A second area of investigation is to analyze the mechanism of PcG protein assemblies in the context of more complex chromatin templates in vitro.

A third area of is to investigate how specific perturbations in the PcG/trxG system affect the chromatin landscape and gene expression in developing Drosophila.

A fourth area is concerned with the role of histone ubiquitylation and deubiquitylation by PcG protein complexes

A fifth focus is to investigate the molecular consequences of particular mutations in PcG proteins that occur in cancer or are the cause of specific congenital disorders in humans.  

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