It is our goal to decipher molecular mechanisms underlying regulation of gene expression during different biological processes such as body pattern formation and haematopoiesis in the model organism Drosophila melanogaster. Currently, we focus on three fundamental topics of gene expression. (i) We investigate how posttranslational modifications of histones contribute to transient and epigenetic regulation of gene expression. (ii) We use DNA microarray-based gene expression and DANN; protien interaction analyses to investigate the functional importance of proteins involved in regulation of gene expression and to dissect the molecular mechanisms involved in differentiation/proliferation of Drosophila hemocytes. (iii) We use biochemical approaches to identify new components of signal transduction pathways, which control the activity of transcription factors/coactivators. To tackle theses aims, we use use a combination of various methods in biochemistry, molecular biology, cell biology, genetics, and DNA microarray
Epigenetic mechanisms play a fundamental role fro development and disease. Our long-term goal is to elucidate the mechanisms underlying epigenetic as a prerequisite for the development of diagnostic and therapeutic assays that detect and attenuate epigenetic-based diseases, respectively. Epigenetic involves the coordinately regulated activity of epigenetic regulators that are recruited to specific DNA elements located in the cis-regulatory region of their target genes. Epigenetic activators bind ‘trithorax-response elements’ (TRE) and repressors contact ‘Polycomb-response elements’ (PRE). The specific hypothesis behind the proposed research is that non-coding RNA transcribed from TRE- and PRE-elements facilitates the recruitment of epigenetic regulators to their target genes and play an essential role in stem cell differentiation. That hypothesis is based on the following observations. First, the TRE- and PRE-elements of target genes for epigenetic regulators are transcribed in vivo. Second, epigenetic regulators of the SET-module family interact with RNA transcribed from TRE- or PRE-elements (termed TRE- and PRE-transcripts) present in the cis-regulatory regions of their target genes. Third, the transient transcription of TRE- and PRE-transcripts restores the interaction of epigenetic regulators with target genes. The specific aims are designed to provide a comprehensive assessment of the functional importance of non-coding RNA for the recruitment of epigenetic regulators to target genes.
The specific aim of the proposed research is to dissect the role and function of the interaction between epigenetic and non-coding RNA in stem cell differentiation. First, we will employ established assay systems to assess the functional significance of detected interactions between epigenetic regulators and TRE- and PRE-transcripts in stem cells by correlating the transcription of TRE- and PRE-transcripts with the recruitment of epigenetic regulators and transcription of cell fate-determining genes and cell differentiation. Second, we will assess whether stem cell differentiation can be actively controlled by transgenic transcription of TRE- and/or PRE transcripts. Accomplishing the aims of this proposal will novel mechanisms underlying stem cell differentiation and novel tools that that can be used to control stem cell differentiation.
See publications on PubMed
Beisel, C. Imhof, A, Greene, J., Kremmer, E., and Sauer, F. (2002). Histone methylation by the Drosophila epigenetic regulator Ash1. Nature 419, 857-861.
Wassarman, D. A., and Sauer, F. (2001) TAFII250: A transcription toolbox. J. Cell Sci. 114, 2895-2902.
Belz, T., et al. (2001) In vitro assays to study histone ubiquitination. Methods 26, 233-244.
Pham, A.-D. and Sauer, F. (2000). Ubiquitin-activating/conjugating activity of TAFII250, a mediator of activation of gene expression in Drosophila. Science 289, 2357-2360.