Epigenetic Regulation (URA CNRS 2578)

Location : 4th floor of the Monod building (building 66), rooms 01 and 07
Mail address :
Monod Building
Institut Pasteur
25, rue du Docteur Roux
75724 PARIS CEDEX 15
FRANCE
Phone : 33 1 45 68 85 25
Fax : 33 1 45 68 89 76

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: A role for abortive transcripts in transcriptional repression?

HP1 proteins are strong transcriptional repressors, which bind to chromatin by associating with methylated histone H3 tails and unknown RNA components. Earlier, we have shown that on the idle HIV1 LTR, recruitment of HP1ß is dependent on transcription by the hypophosphorylated RNA polymerase II that synthesizes an aborted transcript 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. In parallel, we are further characterizing the mechanisms allowing HP1 proteins to bind chromatin. In particular, we find that HP1 proteins contacts not only the histone H3 tails, but also regions inside the nucleosomal barrel, a contact that may function as a sensor of remodeled chromatin. Finally, we are investigating whether HP1 recruitment is affected in human diseases.
Model
Figure 1: 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).

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 (Fig1). We are now examining more generally the implication of histone modifications in the regulation of alternative splicing. In addition, we explore the connections between chromatin and splicing by setting up in vitro transcription-splicing systems on chromatinized templates.

Publications since year 2005

18- Saint-André V, Batsché E, Rachez C & Muchardt C (2010) Histone H3 lysine 9 trimethylation and HP1γ favor inclusion of alternative exons. Nat Struct Mol Biol. 18(3):337-44

17- Lavigne M, Eskeland R, Azebi S, Saint-André V, Jang SM, Batsché E, Fan HY, Kingston R, Imhof A, Muchardt C (2009) Interaction of HP1 and Brg1/Brm with the globular of histone H3 is required for HP1-mediated repression. PloS genetics, 5 (12) : e1000769.

16- Raymond B, Batsche E, Boutillon F, Wu YZ, Leduc D, Balloy V, Raoust E, Muchardt C, Goossens PL, Touqui L (2009) Anthrax lethal toxin impairs IL-8 expression in epithelial cells through inhibition of histone H3 modification. PLoS pathogens 5: e1000359

15- Koga M, Ishiguro H, Yazaki S, Horiuchi Y, Arai M, Niizato K, Iritani S, Itokawa M, Inada T, Iwata N, Ozaki N, Ujike H, Kunugi H, Sasaki T, Takahashi M, Watanabe Y, Someya T, Kakita A, Takahashi H, Nawa H, Muchardt C, Yaniv M, Arinami T (2009) Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia. Human molecular genetics 18: 2483-2494

14- Bourgo RJ, Siddiqui H, Fox S, Solomon D, Sansam CG, Yaniv M, Muchardt C, Metzger D, Chambon P, Roberts CW, Knudsen ES (2009) SWI/SNF deficiency results in aberrant chromatin organization, mitotic failure, and diminished proliferative capacity. Molecular biology of the cell 20: 3192-3199

13- Boukarabila H, Saurin AJ, Batsche E, Mossadegh N, van Lohuizen M, Otte AP, Pradel J, Muchardt C, Sieweke M, Duprez E (2009) The PRC1 Polycomb group complex interacts with PLZF/RARA to mediate leukemic transformation. Genes & development 23: 1195-1206

12- Bierne H, Tham TN, Batsche E, Dumay A, Leguillou M, Kerneis-Golsteyn S, Regnault B, Seeler JS, Muchardt C, Feunteun J, Cossart P (2009) Human BAHD1 promotes heterochromatic gene silencing. Proceedings of the National Academy of Sciences of the United States of America 106: 13826-13831


11- Shen H, Powers N, Saini N, Comstock CE, Sharma A, Weaver K, Revelo MP, Gerald W, Williams E, Jessen WJ, Aronow BJ, Rosson G, Weissman B, Muchardt C, Yaniv M, Knudsen KE (2008) The SWI/SNF ATPase Brm is a gatekeeper of proliferative control in prostate cancer. Cancer research 68: 10154-10162.

10- Mateescu B, Bourachot B, Rachez C, Ogryzko V, Muchardt C (2008) Regulation of an inducible promoter by an HP1beta-HP1gamma switch. EMBO reports 9: 267-272.


9- Allemand E, Batsche E, Muchardt C (2008) Splicing, transcription, and chromatin: a ménage à trois. Current opinion in genetics & development 18: 145-151.

8- Hamon MA, Batsche E, Regnault B, Tham TN, Seveau S, Muchardt C, Cossart P (2007) Histone modifications induced by a family of bacterial toxins. Proceedings of the National Academy of Sciences of the United States of America 104: 13467-13472.

7- Glaros S, Cirrincione GM, Muchardt C, Kleer CG, Michael CW, Reisman D (2007) The reversible epigenetic silencing of BRM: implications for clinical targeted therapy. Oncogene 26: 7058-7066.

6- Auboeuf D, Batsche E, Dutertre M, Muchardt C, O’Malley BW (2007) Coregulators: transducing signal from transcription to alternative splicing. Trends in endocrinology and metabolism: TEM 18: 122-12.

5- 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. Nature immunology 8: 47-56.

4- Coisy-Quivy M, Disson O, Roure V, Muchardt C, Blanchard JM, Dantonel JC (2006) Role for Brm in cell growth control. Cancer research 66: 5069-5076.


3- Batsche E, Yaniv M, Muchardt C (2006) The human SWI/SNF subunit Brm is a regulator of alternative splicing. Nature structural & molecular biology 13: 22-29.


2- Gresh L, Bourachot B, Reimann A, Guigas B, Fiette L, Garbay S, Muchardt C, Hue L, Pontoglio M, Yaniv M, Klochendler-Yeivin A (2005) The SWI/SNF chromatin-remodeling complex subunit SNF5 is essential for hepatocyte differentiation. The EMBO journal 24: 3313-3324.


1- Banine F, Bartlett C, Gunawardena R, Muchardt C, Yaniv M, Knudsen ES, Weissman BE, Sherman LS (2005) SWI/SNF chromatin-remodeling factors induce changes in DNA methylation to promote transcriptional activation. Cancer research 65: 3542-3547.