The establishment and maintenance of mitotically and meitotically stable, epigenetic, gene expression patterns are the hallmark of cell fate determination in metazoans and mistakes in the underlying mechanisms can result in cancerous cell growth. Our long-term goal is to elucidate the regulatory mechanisms directing epigenetic as a prerequisite for the development of diagnostic and therapeutic assays that detect and attenuate epigenetic-based diseases. The specific hypothesis behind the proposed research is that the target genes of epigenetic regulators transcribe non-coding RNA that bind and recruit epigenetic regulators. That hypothesis is based on the observations that 1) DMA elements targeted by epigenetic regulators (TRE-and-PRE-elements) are transcribed in vivo, 2) epigenetic regulators of the SET-module family interact with RNA transcribed from TRE- or PRE-elements, and 3) the transient transcription of TRE- and PRE-elements restores the interaction of epigenetic regulators with target genes in vivo. Based on these observations, the experimental focus of this proposal is on the role of non-coding RNA for the recruitment of epigenetic regulators to target genes.
The specific aims are to: 1. Elucidate the role of non-coding RNA for the recruitment of epigenetic regulators. We will identify the protein- and RNA-motifs that mediate the interaction of RNA transcribed from TRE- and PRE-elements with epigenetic regulators and proteins that retain the RNA at TRE- and PRE-elements. 2. Identify novel interactions between epigenetic regulators and TRE- and PRE-transcripts. TRE- and PRE-elements serve as a target for various groups of epigenetic regulators, implying that RNA from those elements may recruit members of different families of epigenetic regulators. We will identify novel interactions between epigenetic regulators and RNA transcribed from TRE- and PRE-elements. 3. Dissection of the role and function of the interaction between epigenetic and non-coding RNA for development and disease. The recruitment of epigenetic regulators to target genes correlates with development and disease. We will correlate the transcription of RNA from TRE- and PRE-elements in cells and tissues with the recruitment of epigenetic regulators to target genes, cell fate determination in Drosophila, and the aberrant proliferation of mammalian cells.
|Bertani, Stéphane; Sauer, Silvia; Bolotin, Eugene et al. (2011) The noncoding RNA Mistral activates Hoxa6 and Hoxa7 expression and stem cell differentiation by recruiting MLL1 to chromatin. Mol Cell 43:1040-6|
|Gou, Dawei; Rubalcava, Monica; Sauer, Silvia et al. (2010) SETDB1 is involved in postembryonic DNA methylation and gene silencing in Drosophila. PLoS One 5:e10581|