Dr John Halsall PhD

• PhD Cancer Studies and Molecular Medicine, University of Leicester, 2005
• MSc Molecular Pathology and Toxicology, University of Leicester, 2001
• BSc (Hons) Chemistry, University of Warwick, 2000

John graduated from the University of Warwick in 2000 with a degree in Chemistry. Having developed an interest in medicinal chemistry and molecular biology he went on to do an MSc in Molecular Pathology and Toxicology at the University of Leicester. In 2001, John began his PhD, identifying novel genetic variants of the vitamin D receptor gene and studying their role in disease susceptibility and prognosis. John joined the Chromatin and Gene Expression group at the University of Birmingham in 2008 as a postdoc and with Professor Bryan Turner is now leading the group’s research into cellular responses and resistance to epigenetic drugs and the role of histone modifications through the cell cycle.

• MSc Genomic Medicine
• BMedSc (Genes to Therapy Module)
• MSc Clinical Oncology (Translation Research in Cancer Module)
• MRes Cancer Sciences (Genomics Module)

• MRes Molecular and Cellular Biology
• MSc Molecular Biotechnology
• MSc Toxicology

Research in the Chromatin and Gene Expression Group focusses on the role of epigenetic marks, particularly histone modifications, in cellular processes and the response to environmental stimuli.

Current Projects:

Sensitivity and Resistance to Epigenetic Drugs

Histone deacetylase inhibitors (HDACi) are a class of epigenetic drug which have proved remarkably effective against certain types of lymphoma. Epigenetic drugs are now a rapidly growing class of cancer chemotherapeutics but as the number of clinical trials has grown it has become clear that response is patchy and resistance is a problem, particularly in the more common solid tumours.

Histone deacetylase inhibitors cause an increase in the acetylation of histones, the proteins around which DNA is packaged into chromatin. Histone acetylation is associated with active gene expression so it might be expected that treatment with HDACi would lead to a burst of uncontrolled transcription. Instead, Halsall and Turner have shown that the transcriptional response to HDACi is tightly controlled and cells are able to cope remarkably well with the epigenetic disruption.

Halsall & Turner have proposed that cells have an intrinsic resistance response to HDACi which has evolved in eukaryotes in response to exposure to environmental HDACi which are produced by bacteria, including those in our gut, and are also found in the diet.

Tumour cells which are killed by HDACi may have lost their resistance through mutation.

The group’s research is focussed on identifying the components of the resistance response. These represent potential targets for combinatorial therapy as well as markers to allow better targeting of treatment.

Stability and Dynamics of Histone Modifications through the Cell Cycle

The work of the Chromatin and Gene Expression Group has stemmed from Bryan Turner’s ground-breaking work using antibodies to specific histone modifications. These have been used to demonstrate striking patterns of histone modification across chromosomes in dividing cells, when chromosomes are easiest to see microscopically. But what happens to these patterns at other points in the cells cycle? Are modification patterns conserved, perhaps contributing to cellular memory of gene expression patterns as cells divide? Or do patterns change as proteins involved in transcription and DNA replication and repair bind to and move through chromatin?

The group has developed methods to sort cells by cell cycle phase and are using chromatin immunoprecipitation, next generation sequencing and transcriptomics to build up a picture of modification patterns through the cell cycle and how these interact with the timing of transcription, replication and repair.

The Chromatin and Gene Expression Group is part of the Birmingham Centre for Genome Biology.

This video abstract was made to accompany our 2016 Bioessays Hypotheses paper and describes an intrinsic resistance to epigenetic drugs, and an evolutionary rationale for why this resistance should have developed.