|Epigenetic Regulation - Avenir INSERM - URA2578 CNRS|
|HEAD||Dr MUCHARDT Christian / firstname.lastname@example.org|
|MEMBERS||Dr ALLEMAND Eric / AZEBI Saliha / Dr BATSCHE Eric / OLLIVIER Edith / Dr OFICJALSKA Danuta / Dr RACHEZ Christophe / SHARMA Priyanka / SAINT-ANDRE Violaine
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 cloning these ARNs and we are investigating the role of HP1 on cellular promoters pre-recruiting their RNA polymerase II.
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 (Fig. 1). We are now further examining the mechanism allowing SWI/SNF to regulate splicing by setting upin vitrotranscription-splicing systems. In addition, as recruitment of SWI/SNF complexes to genes is dependent on histone modifications, we are investigating a possible epigenetic regulation of alternative splicing.
Keywords: Transcription, chromatin, RNA, splicing, HP1, MAP kinase, AIDS
- Mateescu B, England P, Yaniv M., and Muchardt C, 2004, Tethering of HP1 proteins to chromatin is relieved by phospho-acetylation of histone H3. EMBO Rep.5(5):490-496. PMID: 15105826
- Coisy M., Roure V., Ribot M., Philips A., Muchardt C, Blanchard J-M and Dantonel J-C. 2004, Cyclin A repression in quiescent cells is associated with chromatin remodeling of its promoter and requires Brahma/SNF2alpha. Mol Cell. 2;15(1):43-56. PMID: 15225547
- Batsché, E., M. Yaniv, and C. Muchardt. 2006, The human SWI/SNF subunit Brm is a regulator of alternative splicing. Nat Struct Mol Biol 13:22-29. PMID: 16341228.
- 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. 8(1):47-56. PMID: 17159983
- Mateescu B., Bourachot B., Rachez C., Ogryzko V., and Muchardt C.Regulation of an inducible promoter by a HP1ß-HP1γswitch. EMBO rep 2007. In press.
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