Epigenetic Regulation - CNRS FRE 2850– INSERM Avenir  

  HEADDr MUCHARDT Christian / muchardt@pasteur.fr
Dr RACHEZ Christophe / SAINT-ANDRE Violaine

  Annual Report

Over the recent years, several fascinating discoveries have revealed an implication of RNA molecules in the regulation of chromatin condensation and transcription. A connection between RNAs and factors regulating transcription is not surprising as RNA is by definition an integer component of the transcription machinery. However, our knowledge of this connection is still very restricted and there is a clear need of a more comprehensive characterization of the crosstalk between the transcription machinery and the RNAs that this machinery produces. The objective of our group is to investigate this crosstalk, defining the proteins, the RNAs and the mechanisms involved, in an attempt to achieve an overview on its impact on transcriptional regulation in a broad sense.

We focus on both short and long RNAs:

Short RNAs: An RNAi-dependent mechanism of transcriptional repression in mammals?

In S. pombe, siRNAs can target chromatin-modifying complexes to sites of transcription and induce repression. Using the HIV-1 LTR as a model promoter, we have investigated whether a similar mechanism may exist in mammalian cells. We find that the RNAi machinery is required for the recruitment of HP1 proteins that function as strong transcriptional repressors. The possible implication of the short stem-loop-structured TAR RNA produced by the non-induced HIV-1 promoter is currently under scrutiny. We expect our data to provide insight on retroviral latency. Besides, several cellular promoters are suspected to be regulated via similar mechanisms in particular genes involved in the innate immune response.

Long RNAs: Control of alternative splicing by chromatin regulating factors?

Alternative splicing is a major source of diversity for the proteome. It is regulated by the very complex spliceosomes but also by several factors involved in transcription. These factors can affect maturation of the transcripts because splicing is initiated while transcription is still on going. Recently, we have shown that the human chromatin remodeling complex SWI/SNF can favor inclusion of alternative exons by affecting the elongation rate of the RNA polymerase II (Fig. 1). As recruitment of SWI/SNF complexes to genes is dependent on histone modifications, we are currently investigating a possible epigenetic regulation of alternative splicing.


Figure: Le complexe SWI/SNF humain participe à la régulation de l’inclusion d’exons variants en réduisant la vitesse d’élongation de l’ARN polymérase II. Cette réduction de la vitesse favorise cinétiquement les donneurs d’épissage faibles dont la séquence diverge du consensus.

Figure : The human SWI/SNF complex regulates exon inclusion on the CD44 gene by reducing the elongation rate of the RNA polymerase II and thereby kinetically favoring the use of suboptimal splice donors (Batsché et al., Nat. Struc. Mol. Biol, 2006).


Publications 2006 of the unit on Pasteur's references database

Activity Reports 2006 - Institut Pasteur
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