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Epigenetic Regulation of Gene Expression

The overall aim of our group is to understand how epigenetic mechanisms, including histone modifications and non-coding RNAs, control the transcription of genes. We are driven by the fact that deregulation of these mechanisms leads to diseases such as cancer. To accomplish the above research aim we employ interdisciplinary approaches including molecular biology, biochemical, genetic, genomic and proteomic techniques using both mammalian and yeast cells as model systems.

Histone modifications:

In every eukaryotic cell the genome is packaged into chromatin which is mainly composed of the DNA and the histone proteins. The organization and structure of chromatin within the nucleus can regulate the transcription of DNA. Post-translational modifications placed on histone proteins, such as methylation, acetylation and phosphorylation, can influence the configuration of chromatin and ultimately control DNA accessibility by the transcriptional machineries. Several cellular enzymes have been discovered so far that can deposit or remove modifications on histones. Therefore, histone modifying enzymes and their underlying modifications play a crucial role in the regulation of gene expression. Driven by the fact that many of these histone modifiers are frequently mutated or lost in human cancer our group is interested in understanding the molecular mechanisms employed by these enzymes and their underlying modifications during gene regulation. Of particular interest to our research are the enzymes that methylate arginine residues on histone proteins known as protein arginine methyltransferases (PRMTs). Our previous work has begun to unravel the precise molecular mechanisms by which histone arginine methylation and the associated PRMTs modulate gene activity (Figure 1). To further our knowledge on this epigenetic mode of gene regulation our current work is focused in three main areas:

1) Identify and characterise novel regulators of histone arginine methylation.
2) Determine the interplay of histone arginine methylation with other modifications during gene expression.
3) Investigate the mechanistic link among histone arginine methylation, PRMTs and the development of cancer.

Figure 1: Regulation of gene expression by histone arginine methylation. Methylation at arginine 2 on histone H3 (H3R2) by PRMT blocks methylation at lysine 4 (H3K4) by Set1. Removal of H3R2 methylation by a currently unknown arginine demethylase or histone replacement allows methylation of H3K4 and induction of gene expression

Non-coding RNAs:

Recent genomic technologies have revealed genome-wide pervasive transcription in many eukaryotic organisms during which many non-coding RNAs (ncRNAs) are generated (Figure 2). In budding yeast approximately 85% of the genome is transcribed, as indiated by our histone modification profiles (see Data). This widespread transcription leads to the production of various types of ncRNAs including antisense transcripts that overlap coding sequences and transcripts synthesized within regions with no previous annotated features. Many of these non-coding RNAs are rapidly degraded in yeast and were appropriately named CUTs (cryptic unstable transcripts) or XUTs (Xrn1-sensitive unstable transcripts). There is also another class that is not targeted for degradation and hence called SUTs (stable unannotated transcripts). Initial hypothesis proposed that these non-coding transcripts are just a result of transcriptional noise. However, more recent evidence suggests that at least some of these ncRNAs are functional and play a role in regulating DNA-based processes such as expression of protein-coding genes. Hence our lab is addressing the following research objectives:

1) Determine the biological function of some of these ncRNAs.
2) Identify the precise molecular mechanisms by which these ncRNAs may regulate gene expression.


Figure 2: Profiling of histone modifications in yeast. Genome-wide distributions of the three methylated states of histone H3 lysine 4 (H3K4) have been analysed using the ChIP assay coupled to high-resolution microarrays (see Data). Their distribution indicates the activity of protein-coding genes (blue arrows) and the orientation of transcription. For example, H3K4me3 highly correlates with active genes and is found at the 5’-end of transcribed regions. Novel transcriptional units (brown arrow) have been revealed within unannotated regions, which were subsequently shown to transcribe non-coding RNAs.

Achieving the above research goals will provide important clues to better understand how these epigenetic factors contribute to the cell function. Our long–term goal is to apply the information acquired on the basic biology of histone arginine methylation, PRMTs and non-coding RNAs towards the development of therapeutic targets and diagnostic tools for cancer.
Kirmizis Lab • Biological Sciences • Univeristy of Cyprus • 1 University Avenue • 2109 Aglantzia • Nicosia • Cyprus
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