Role of polycomb proteins in gene transcription, stem cell and human diseases

Published on February 4, 2014   37 min

Other Talks in the Series: Epigenetics, Chromatin, Transcription and Cancer

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Role of Polycomb Proteins in Gene Description, Stem Cells and Human Diseases, by Luciano Di Croce, from the Gene Regulation, Stem cell, and Cancer Department, ICREA, and Center for Genomic Regulation, Barcelona, Spain.
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The DNA of eukaryotic cells is organized in chromatin fibers, where the nucleosome forms the basic repeating unit. Each nucleosome comprises 147 base pairs of DNA, which is wrapped in 1.8 elegant turn around an octamer of four highly [INAUDIBLE] conserved histone protein, which are histone H two A, histone H two B, histone H three, and histone H four. These four structure, which is often called as 11 nanometer fibers. The histone H1 lines to deliver DNA between two addition nucleosomes, causing further compaction of the chromatin fibers into higher order structure, often refer as a solenoid or as 30 nanometer fibers. The analyses of the crystal structure of the nucleosome, which was solved in 1998 by the group of Luger and Richmond, reveal that on terminal a part of the histone tail are flexible and protrude outside from the nucleosome core. The histone tail undergoes a large number of post-translational modifications.
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Some of these modifications are illustrated in this slide. For example, lysine can be acetylated, methylated, while arginine can also be methylated. Serine and threonine can be phosphorylated. Lysine can be also to be ubiquitinated or sumoylated and so forth. Too many functions have been ascribed for histone modifications. For example, acetylation of lysine neutralizes the positive charge at histone tail. And two, altering histone DNA interaction reduces interaction between different histones, in addition to nucleosomes. Moreover, as illustrated in the bottom part of this slide, several post transcriptional modifications of histones generate docking side, or modulate the affinity of nuclear proteins for chromatin. The specific recognition of histone modification is achieved by a dozen protein domains, which are present in a large number of chromatin-associated proteins. In turn, these adaptive proteins are usually part of large protein complexes, implicated in chromatin remodeling, prescription, or for further modifications of histone tails.
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Enzymes responsible for several of histone modifications have identified. In this slide, I've represented the enzyme responsible for modification of lysine four, lysine nine, lysine 27, lysine 36, and lysine 79. In the upper part of the slide are represented the histone methyltransferases, which are responsible for depositing the methyl group on those lysines. While, in the bottom part of the slide, I've represented the enzyme which are responsible for removing the methyl group for those lysines.
3:33
With respect to lysine methylation, the situation is a bit more complex. Indeed, lysine can be either monomethylated, dimethylated, or trimethylated. And this has important physiological consequences. For example, when the lysine is trimethylated, a protein may have high affinity toward this modification-- while, if the lysine is dimethylated, the affinity for the protein can be reduced. Or, as an extreme case, when it is monomethylated, the protein could be unable to bind to this modification, while the specific modification can be recognized by a different class of protein, as depicted here in orange.
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The enzyme responsible for the posting the material group on lysine 27 are the Polycomb complexes. Polycomb group of proteins, where originally identified in Drosophila, is a group of proteins which counteract the activity of Trithorax in controlling the expression of several genes, including the hox genes. These protein complexes are important not only for gene regulation, but also play an important role in animal development and, as we will see soon, also in stem cell differentiation. While Trithorax group of proteins activates transcriptions of target genes, Polycomb proteins are repressors. Importantly, recent data suggests that misregulation of Polycomb proteins is often involved in tumoral genesis. The composition and the function of both Trithorax group of proteins and Polycomb group of proteins is conserved from Drosophila to mammals. As indicated in the slide, the Polycomb complexes come in two flavors-- the Polycomb Repressive Complex One and the Polycomb Repressive Complex Two, which core proteins are illustrated at the bottom of the slide.
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Role of polycomb proteins in gene transcription, stem cell and human diseases

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