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Title: Characterisation of a histone deiminase
Author: Cuthbert, Graeme Lachlan
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2005
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Transcription of chromatin template requires rapid and reversible alterations to nucleosomal structure and spacing. This dynamic regulation is achieved by the co-ordinated action of multiple enzyme activities including those that adjust the position of nucleosomes and those that covalently modify histones. Histone acetylation, phosphorylation and ubiquitination are known to be reversible, concordant with a model in which such modifications act as switches between permissive and repressive states. However, methylation of lysine and arginine residues in histones was thought to be irreversible and has been suggested to act as an epigenetic memory. This theory has been called into question by the recent discovery of a lysine demethylase, and the suggestion that arginine may be demethylated by its conversion to citrulline (deimination). I show that a candidate histone arginine deiminase, peptidyl deiminase 4 (PADI4), converts arginine residues in the tail of histone H3 to citrulline. PADI4 is active on both unmethylated and mono-methylated substrates, but not di-methylated substrates. Once converted to citrulline, residues are no longer substrates for the arginine methyltransferase CARM1. Targeting PADI4 to an endogenous promoter specifically blocks activation by nuclear receptors. Consistent with this, endogenous PADI4 and deiminated histone H3 occur between transcriptional cycles of an estrogen-stimulated promoter in vivo. PADI4 is also capable of deiminating another arginine-methylated substrate, the methyl-CpG binding protein MeCP2. These results suggest that deimination of arginine residues is a novel mechanism by which transcription is regulated and that at least one arginine demethylating pathway exists.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available