AbstractIn response to low oxygen (hypoxia), cells have evolved sophisticated gene expression programmes for survival and adaption. How the chromatin state coordinates these changes remains largely unknown. Global histone methylation changes occur in response to hypoxia, however, temporal dynamics of histone methylation changes and how they correlate with hypoxia induced gene transcription changes is ill defined. The Jumonji C (Jmjc) histone demethylases are oxygen dependent enzymes and represent a potential link between chromatin structure and oxygen sensing. Many of these enzymes are differentially expressed in hypoxia and some have been found to influence the hypoxic response.
Here, the JmjC histone demethylase, KDM2B, is found to be induced at the mRNA level but not at the protein level in response to hypoxia. KDM2B was also found to regulate the transcriptional response hypoxia, in a cell type dependent manner, through control of Hypoxia Inducible Factor (HIF) subunits, HIF 1 and 2α. These findings highlight complex HIF-KDM2B crosstalk involved in the cells response to low oxygen. Additionally, it was found that various histone methylation marks are induced in the early response to hypoxia prior to hypoxia induced gene transcription changes. This demonstrates that chromatin structural marks responds rapidly to changes in oxygen availability. Furthermore the methylation landscape of 2 two active transcription histone methylation marks, H3K4me3 and H3K36me3, were mapped by ChIP sequencing in the acute response to hypoxia. This analyses found specific changes in histone methylation, which correlate with the core gene transcription changes in hypoxia, pointing towards a mechanism by which rapid chromatin changes programs the cell for hypoxic transcription. Finally, KDM5A was identified to, at least in part, regulate early hypoxia H3K4me3 changes and changes in gene expression of a subset of hypoxia responsive genes.
Findings described herein provide evidence for the role of chromatin structure dynamics, mediated by chromatin modifying enzymes, in regulating the hypoxic response. Specifically, early histone methylation changes elicited in acute hypoxia may help establish a chromatin landscape for the cell to transcriptionally respond, which is essential for survival and adaptation to hypoxia. Insights into chromatin dynamics in the response to hypoxia and the role played by JmjC histone demethylases in regulating the hypoxic response has the potential for new drug discovery in diseases such as cancer, were hypoxia, epigenetics and JmjC enzymes are often implicated in disease progression.
|Date of Award||2017|
|Supervisor||Sonia Rocha (Supervisor)|
- Gene regulatory networks