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Dr. Chiara Lanzuolo


Tuesday, July 3rd, 2012 at 11:00:00 AM  

Conference room Querzoli - LENS - via Nello Carrara 1 - Sesto Fiorentino (Florence)

Published on-line at 11:34:47 AM on Thursday, June 28th, 2012

Epigenetic signatures in cancer

The epigenetic silencing of genes during embryonic development allows for the terminal differentiation that is essential for complex body plans.

Complex higher-order structures found in the cell nucleus serve to compact areas of chromatin so that it is no longer transcriptionally active. One such group of structures, called Polycomb bodies, are composed of Polycomb group (PcG) gene products, Polycomb response elements (PREs), and specific gene promoters that interact to regulate the suppression of key developmental genes by altering the physical conformation of chromatin into loops (Lanzuolo et al., 2007).

In humans, PcG proteins are key epigenetic regulators of chromatin architecture in the nucleus that act as transcriptional repressors. PcG proteins regulate large numbers of target genes, primarily those involved in differentiation and development (Richly et al., 2011). In the nucleus, PcG proteins are organized as microscopically visible foci called PcG bodies. Recently, it has been shown that PcG bodies are highly dynamic during embryogenesis, suggesting a correlation between the flexibility of chromatin structures and the potential for cell differentiation (Cheutin and Cavalli, 2012).

The biothrax complex (BX-C) is a ~300 kb locus of DNA that controls posterior thorax development in Drosophila. In the repressed state, the BX-C locus adopts a condensed structure in which all the Polycomb group (PcG)-bound elements are interacting together. In this conformation, all Polycomb response elements (PREs; orange in the figure), promoters (light blue) and 3' ends of the genes (green) organize the BX-C in topologically discrete domains. In cells with a constitutively active AbdB gene, the PRE-promoter interaction, observed in the context of repression, is lost, whereas the other epigenetic elements that are still silenced retain their clustered conformation. Figure taken from Lanzuolo et al., Nature Cell Biology, 2007.

These complexes have also been shown to be upregulated in several human cancers, including breast, bladder, colon and prostate cancers. PcG proteins function to suppress the transcription of tumor suppressor genes, and their overexpression leads to uncontrolled proliferation, malignant transformation and changes in cancer progression.

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For further informations, please contact Dr. Blaine Bisel.