Spatio-Temporal Regulation of Transcription in Eukaryotes
Our group is studying the molecular mechanisms involved in the transcriptional regulation of nuclear receptor target genes. More precisely, we focus on the dynamics of these regulations, both in space and time. Our aim is to describe the sequences of events allowing a cell to acquire a specific transcriptome, which deregulation can initiate cancer.
Keywords: Transcription, Nuclear Receptors, Chromatin, …
Our genome comprises about 35,000 genes, inherited from our parents. This genetic heritage brings a unique set of genes to generate a complex organism exhibiting many different tissues which all have distinct phenotypes. This specialization of our 10,000 billion cells is created by the transcription of only a given part of our genes in every cell type. In addition, cells can adapt their transcriptome to new requirements in response to environmental signals such as electric stimuli in the case of neurons, or soluble circulating signals like hormones and growth factors.
The genome of eukaryotic cells is highly organized in at least three dimensions. First, within the cell nucleus, DNA is packed into a nucleoprotein complex termed chromatin, which is intrinsically organized as a succession of nucleosomes. In each nucleosome, 146 bp of DNA is wrapped around an histone octamer including two of each H2A, H2B, H3 and H4 histones. Chromatin can be physically and functionally separated into condensed heterochromatin that includes silent/repressed genes, and euchromatin which is less condensed and comprises transcriptionally active genes. These two states are maintained through numerous protein/protein and DNA/protein interactions established as a readout of epigenetic marks such as post-translational modifications of histones or DNA methylation. The epigenome thus generates spatial and functional constraints that complement genetic instructions in regulating gene activity.
Processes that regulate transcription do have to interpret both genetic and epigenetic informations. In itself, gene transcription requires many proteins to be recruited onto chromatin. Some of these in turn modify chromatin in order to generate three-dimensional organizations that are permissive for the mobilization of other protein components. This plasticity of chromatin relies on the incorporation of histone variants, remodeling of nucleosome positioning and stability, as well as on post-translational modifications of histones. Besides these highly dynamical processes, spatial reorganizations of genes inside the nuclear volume participate in the resetting of a transcriptome.
One forthcoming and required stake in the field of transcription is now to integrate all these epigenetic parameters into our current view of how the transcriptome is established and regulated. Research performed by members of the SPARTE group is focused on these objectives. [More]