Transcription regulation through chromatin structure and nuclear compartmentalization

Ferrai, Carmelo (2007). Transcription regulation through chromatin structure and nuclear compartmentalization. PhD thesis The Open University.



Transcription is a very complex multi-step process presenting different levels of regulation. A large amount of general transcription factors and cofactors recruited on the promoters participate, together with the polymerases, in driving RNA production. The formation of chromatin loops allows their interaction with specific transcription factors bound to distant regulatory sequences and the fine tuning of the gene activity. A further level of complexity is provided by the structural and functional compartmentalization of the nucleus. In fact gene transcription takes place in a strongly localized fashion and nuclear architecture can influence genome regulation. One of the most intriguing findings is that an acto-myosin network plays a role in gene transcription. However, the in vivo role of such proteins in gene expression is still largely unclear. During my PhD I developed a technical approach coupling MNase digestion to ChIP by which I showed that the enhancer and minimal promoter of the human uPA gene function as a single transcription control unit forming a stable structure, that is required to sustain the early elongation step of RNAP-II. I next studied the uPA gene in an inducible cell system showing that it is associated with an inactive RNAP-II transcription factory before the onset of its expression while transcriptional induction promotes its association with an active transcription factory. This finding indicates inactive factories as distinct entities from the active ones supporting the notion of specialized transcription factories. I also studied the involvement of MyosinVI in transcription, characterizing its role in regulating RNAP-II activity. MyosinVI is required for phosphorylation of RNAP-II CTD at level of Serin-2 that, in turn, is required for the enzyme to proceed in the elongating phase. Finally, I showed that the transcription factor Prep1 and MyosinVI are associated in a complex and that the recruitment of MyosinVI on the Prep1-target genes is mediated by the transcription factor itself.

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