Chromatin structure will be discussed in two aspects, namely the epigenetic histone phosphorylation in human cells and the application of recombinant chromatin as a drug delivery vehicle. First aspect is about mitogen- and stress-activated kinase 1 (MSK1) that is a histone H3 kinase involved in an activator-dependent transcription. We investigated the function of MSK1 in regulating target gene expression by p53 tumour suppressor.
Our results showed that physical interaction with p53 enables MSK1 to phosphorylate histone H3 and that activated MSK1 displays increased coactivator function. We also found that the constitutively active MSK1 mutants without proper post-translational modifications have a defect in transactivation. Our study suggests that MSK1 is a critical transcriptional coactivator of p53 and that MSK1 activation by upstream MAPK signals is important for efficient p53 target gene expression.
The second aspect is about a pharmaceutical application of recombinant chromatin. Given a well-defined structure of nucleosomes, we hypothesised that therapeutic peptides derived from cancer-specific antigens can be displayed on the outside of chromatin fibre to raise a protective immune response against tumours. To test our working hypothesis, we have incorporated the 17 amino acid-length peptide of oncogenic RAS (G12V) at the N-terminus of individual histones of chromatin.
The recombinant chromatin displaying G12V peptide (G12V-chromatin) has a comparable structure to the wild type chromatin and highly stable up to 4 months of storage. G12V-chromatin itself without an adjuvant did not induce a detectable immune responses in mice after standard vaccination procedure. Upon combined administration with monophosphoryl lipid A, G12V-chromatin induced a higher G12V-peptide specific antibody response than G12V-histone.
However, G12V-chromatin appears not activate T cell response based on a γ-interferon response, implying that peptide-chromatin fusion fails to engage in a peptide-TCR interaction.
Our result indicates that multiple peptide display on the chromatin serves as an effective B cell agonist probably through an interaction of multiple BCR with the repeated peptide epitopes on the chromatin, without necessarily involving T cell stimulation.
|Date||Friday, 21 June 2019|
|Time||1:00pm - 2:00pm|
|Event Category||Health Sciences|
|Location||D'ath Lecture Theatre, Hercus Building|
|Contact Name||Dr Euan Rodger|