Use this URL to cite or link to this record in EThOS:
Title: JAK-STAT signalling at chromatin
Author: Dawson, M. A. F.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2010
Availability of Full Text:
Full text unavailable from EThOS.
Please contact the current institution’s library for further details.
The aim of my work was to explore the possibility that the mammalian JAK2 signalling pathway influences the structure and function of chromatin. I have demonstrated that JAK2 is present in the nucleus of both human haematopoietic cell lines and primary cells. My results suggest that JAK2 functions as a histone tyrosine kinase and phosphorylates histone H3 at tyrosine-41 (H3Y41). This novel histone modification, the first described tyrosine phosphorylation on any of the non-variant histones, regulates the binding of heterochromatin protein 1-alpha (HP1α) at a new binding site on chromatin. HP1α uses its chromo-shadow domain to bind the H3Y41 region. Phosphorylation of H3Y41 by JAK2 reduces its affinity for chromatin. This reciprocal relationship was given a functional context by demonstrating its relationship to the expression of a key haematopoietic oncogene Imo2. Genome-wide studies demonstrate that H3Y41ph is present at the 5’ end of genes and is highly correlated with active transcription. This is the first comprehensive genome wide mapping of a histone phosphorylation mark and potentially highlights a role for this novel modification in the regulation of transcription. H3Y41ph was also present at specific cis-regulatory elements on JAK2-STAT5 target genes and genome-wide mapping of STAT5 binding confirmed that STAT5 binding and H3Y41ph was coincident at a significant number of sites within the human genome. This interesting observation suggests that canonical JAK2-STAT5 signalling is not confined to the cytoplasma but also occurs at chromatin. These findings extend the existing paradigm of JAK-STAT signalling and provide a platform for a better understanding of this critical signalling pathway, which is important in both normal development and oncogenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available