Epigenetic Regulation - URA2578 CNRS – INSERM AVENIR  


  HEADDr. MUCHARDT Christian / christian.muchardt@pasteur.fr
  MEMBERSDr. ALLEMAND Eric / AZEBI Saliha / Dr. BATSCHE Eric / JANG Suk-Min / Dr. OFICJALSKA Danuta / OLLIVIER Edith / Dr. RACHEZ Christophe / Dr. SHARMA Priyanka / 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 RNA-dependent mechanism of transcriptional repression in mammals ?

HP1 proteins are strong transcriptional repressors, which bind to chromatin by associating with methylated histone H3 tails and unknown RNA components. These proteins are present on the HIV-1 LTR during phases of viral latency. We have shown that on this promoter, recruitment of the HP1ß isoform is dependent on transcription by the hypophosphorylated RNA polymerase II that at this time transcribes a short regulatory RNA known as TAR. These observations suggest that the RNA components bound by HP1 proteins may be the product of non-elongating polymerases that are now known to be present on many promoters. Currently, we are investigating the role of HP1 on inducible cellular promoters pre-recruiting their RNA polymerase II. We are also examining the mechanisms allowing HP1 to repress transcription and investigating whether HP1 recruitment is affected in human diseases.

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 ongoing. Earlier, 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. The effect of SWI/SNF on splicing has been pursued at a genome-wide scale. The mechanism of this effect is further examined by setting up in vitro transcription-splicing systems. More generally, we are also investigating a possible implication of histone modifications in the regulation of alternative splicing. modifications, we are currently investigating a possible epigenetic regulation of alternative splicing

Keywords: Transcription, chromatin, RNA, splicing, HP1, MAP kinase, AIDS

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  Publications

Allemand E, Batsché E, Muchardt C. (2008) Splicing, transcription, and chromatin: un ménage à trois. Curr Opin Genet Dev. 18(2):145-51.

Mateescu B, Bourachot B, Rachez C, Ogryzko V, Muchardt C. (2008) Regulation of an inducible promoter by an HP1beta-HP1gamma switch. EMBO Rep. (3):267-72.

Hamon MA, Batsché E, Régnault B, Tham TN, Seveau S, Muchardt C, Cossart P. (2007) Histone modifications induced by a family of bacterial toxins. Proc Natl Acad Sci U S A. 104(33):13467-72. Erratum in: Proc Natl Acad Sci U S A. 104(44):17555.

Arbibe L, Kim DW, Batsche E, Pedron T, Mateescu B, Muchardt C, Parsot C, Sansonetti PJ. (2007) An injected bacterial effector targets chromatin access for transcription factor NF-kappaB to alter transcription of host genes involved in immune responses. Nat Immunol. (1):47-56.

Batsché E, Yaniv M, Muchardt C. (2006) The human SWI/SNF subunit Brm is a regulator of alternative splicing. Nat Struct Mol Biol. (1):22-9.





Activity Reports 2009 - Institut Pasteur
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