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Title: Epigenetic control of human HOX clusters
Author: Sessa, Luca
ISNI:       0000 0001 3394 3994
Awarding Body: Open University
Current Institution: Open University
Date of Award: 2004
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In Drosophila, Polycomb group (PcG) and trithorax group (trxG) genes are part of a cell memory system that prevents changes in cell identity by maintaining transcription patterns starting from the developing embryo throughout adult stages. PcG and trxG control epigenetically repressed and active transcriptional states of Hox genes and developmentally regulated genes. Both PcGs and trxGs exert their functions by binding to specific DNA element called Polycomb/Trithorax Response Elements (PREs/TREs). Many PREs were identified and characterized in the BX-C of D. melanogaster. Since no human PREs/TREs have been identified, we decided to map PcG/trxG protein distribution in human HOX loci. Sequence comparisons "in silico" revealed that HOX clusters present a unique redistribution of the Repetitive Elements (REs) which localize in the flanking regions and are absent from the inner part of the cluster. Mapping of PREs/TREs by chromatin immunoprecipitation (X-ChIP), revealed that PcGs/trxG proteins associate with RE-containing fragments at the boundaries of the human HOXA cluster. We discuss the possibility that REs could modulate Hox gene expression by working as epigenetic elements able to nucleate the formation of heterochromatin-like structures. PRE/TRE characterization in D. melanogaster showed that PcG and trxG proteins could interact with the same DNA element, implying that these elements could work both as a PRE and as a TRE. Recently it has been hypothesized that the switch from PRE to TRE involves the transcription of these intergenic modules. As for other genetic phenomena (X-chromosome inactivation, dosage compensation, genomic imprinting), these non-coding RNAs play a role in epigenetic control of gene expression, suggesting that non-coding transcripts may underscore the position of cis-regulatory elements. I then investigate about 400 genomic loci for the presence of non-coding intergenic RNAs. Among the others, I have identified and characterized these non-coding transcripts in intergenic regions of human and mouse homeotic loci.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral