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Title: Mechanisms of transcriptional regulation by SRF co-factors
Author: Gualdrini, F.
ISNI:       0000 0004 5364 7588
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2015
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Serum response factor (SRF) controls gene activation in response to changes in actin dynamics and mitogen-activated protein kinases. SRF has low intrinsic transcriptional activity and requires the recruitment of one of two families of co-activators: the MRTFs (myocardin-related transcription factors) and the TCFs (ternary complex factors). MRTFs are actin-binding proteins. Disruption of the actin-MRTF interaction is sufficient to induce MRTF nuclear accumulation and transcriptional activation. The TCF family are specifically activated by MAPK signalling. This thesis aims to elucidate how the SRF transcription network is controlled. The work presented encompasses two projects focused on each of the co-activator families. The regulation of MRTF shuttling from the cytoplasm to the nucleus is relatively well understood while its regulation once in the nucleus is still uncharacterized. The work demonstrates that nuclear MRTF activities are influenced by nuclear actin. Nuclear actin interferes with MRTF-DNA binding and target gene activation. In the presence of G-actin, nuclear MRTF can associate with target loci and recruit Pol II that, although traverses the gene body, does not generate stable mRNA. This inhibited state is accompanied by hypo-phosphorylation of the Pol II CTD. Dissociation of MRTF-actin interaction is required to re-establish Pol II phosphorylation and mRNA accumulation. The Erk-TCF signalling pathway was used to investigate how chromatin signatures are established in response to cues. Fibroblasts lacking all three TCFs, or reconstituted with mutant derivatives of the Elk-1 TCF were generated. Following Erk activation, chromatin immunoprecipitation and RNA-sequencing techniques, were employed to study the role of the TCFs in chromatin changes and transcriptional activation. It was possible to show that signal-induced chromatin changes occur in absence of transcription, and the specific chromatin signature requires Elk-1 DNA binding and phosphorylation. In addition analysis of the H3K27me3 mark demonstrated that Elk-1 activation is required to maintain a permissive chromatin landscape.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available