Objective More than 70% of the human genome synthesizes non-coding RNA that is believed to regulate gene expression. While there is ample evidence from model systems that small RNAs are the lynchpin of powerful mechanisms that silence transcription, the demonstration of transcriptional gene silencing (TGS) mediated by a small RNA in humans is lacking. We have recently shown that the HIV-1 LTR is controlled by premature termination of transcription and TGS mediated by a small RNA derived from the stem-loop structure, TAR, that forms the 5’ end of HIV-1 transcripts. This pathway depends on Microprocessor, Xrn2, Setx and Rrp6. Cleavage of TAR by Microprocessor has major consequences 1) it provides a substrate for Rrp6, which generates a small RNA that represses HIV-1 transcription, 2) it creates an entry site for Xrn2 and termination factors that lead to premature termination of transcription. Loss of Microprocessor or Rrp6 leads to recruitment of RNAPII to the LTR and activation of transcription. These findings not only provide the first evidence showing that small RNA-mediated TGS acts in human cells, but they also uncovered a new mechanism of gene regulation involving premature termination of transcription by RNAPII. Several important questions now need to be answered. What is the mechanism underlying small RNA-mediated TGS? Does small RNA-mediated TGS operate at human genes? What is the contribution of TGS coupled to premature termination in the global control of transcription? We will use a battery of biochemical and molecular approaches to dissect the molecular mechanism of RNA-mediated TGS. The global importance of small RNA-mediated TGS and premature termination of transcription in the control of human gene expression will be addressed using complementary genome-wide approaches. RNA-mediated TGS coupled to premature termination, if confirmed as a widespread mechanism controlling transcription, will fundamentally change our perspective of transcriptional control in humans Fields of science engineering and technologyelectrical engineering, electronic engineering, information engineeringelectronic engineeringcomputer hardwarecomputer processorsnatural sciencesbiological sciencesgeneticsRNAnatural sciencesbiological sciencesgeneticsgenomes Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) ERC-CG-2013-LS2 - ERC Consolidator Grant - Genetics, Genomics, Bioinformatics and Systems Biology Call for proposal ERC-2013-CoG See other projects for this call Funding Scheme ERC-CG - ERC Consolidator Grants Host institution CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS EU contribution € 1 999 974,00 Address RUE MICHEL ANGE 3 75794 Paris France See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Administrative Contact Guillaume Rochet (Mr.) Principal investigator Rosemary Elizabeth Kiernan (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data Beneficiaries (1) Sort alphabetically Sort by EU Contribution Expand all Collapse all CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS France EU contribution € 1 999 974,00 Address RUE MICHEL ANGE 3 75794 Paris See on map Region Ile-de-France Ile-de-France Paris Activity type Research Organisations Administrative Contact Guillaume Rochet (Mr.) Principal investigator Rosemary Elizabeth Kiernan (Dr.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
