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Coordinated regulation of transcriptional repression by the RBP2 H3K4 demethylase and the Polycomb Repressive Complex 2

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Polycomb Group (PcG) proteins are transcriptional repressors essential for development and for cellular proliferation. PcG proteins play a central role in the establishment of specific transcription programs that regulate cell fate determination during development by the direct regulation of the expression of a large number of genes essential for proper development. Despite this, little is still known about the molecular mechanisms by which PcG proteins regulate genes expression.

Differentiation into different committed cell types starting from the same genetic information is achieved trough an epigenetic regulation of transcription. Post-translational modifications of Histone N-terminal tails play an essential role in this process and factors that place or recognize these modifications are required for cell identity during development and are frequently found deregulated in human cancers.

PcGs are divided in two distinct mutiprotein complexes named Polycomb Repressive Complex (PRC) 1 and 2. The PRC2 complex, through its subunit EZH2, catalyzes the tri-methylation (me3) of Histone H3 on Lysine (J) 27. The mechanisms by which the PRC2 complex and H3K27 methylation induce transcriptional silencing are still unknown but the PRC2 activity is required for different epigenetic phenomena such as X-chromosome inactivation and genes imprinting, is essential for development and is frequently deregulated in human tumors.

The discovery of Histone Lysine Demethylases that catalyze the active removal of methyl groups from Lysine residues, demonstrated that lysine methylation is no longer a stable modification. This discovery has introduced an additional layer of complexity in the mechanisms of epigenetic regulation of transcription. Recently, others and we have identified RBP2 (JARID1A) as a specific H3K4me3 de-methylase that is required for homeotic genes expression and worm development. Despite this, nothing is known about the pathways and the molecular mechanisms by which Rbp2 regulates transcription.

We will present data demonstrating a functional interplay in mouse Embrionic Stem (es) cells between the PRC2 complex and the H3K4me3 demethylase Rbp2. By genome-wide location analysis we have found that Rbp2 is associated with a large number of PcG target genes in mouse ES cells. We will show that the PRC2 complex recruits Rbp2 to its target genes and that this interaction is required for PRC2-mediated repressive activity during ES cell differentiation. Taken together, our results demonstrate an elegant mechanism for repression of developmental genes by the coordinated regulation of epigenetic marks involved in repression and activation of transcription.
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Document Type: Abstract

Publication date: May 1, 2008

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