Dr John Halsall PhD

Dr John Halsall

Institute of Cancer and Genomic Sciences
Research Fellow

Contact details

Address
Chromatin and Gene Expression Group
Institute of Cancer and Genomic Sciences
University of Birmingham
Edgbaston
Birmingham
B15 2TT

John Halsall is a Research Fellow in the Chromatin and Gene Expression Group. His research centres on how epigenetic marks, particularly histone modifications regulate the interaction of the genome with cellular processes and external stimuli, particularly epigenetic drugs.

He is studying the mechanism of action of epigenetic drugs, a rapidly growing class of cancer chemotherapeutics. In particular he is interested in why certain cancers are resistant to these drugs and how this resistance might be targeted to increase treatment efficacy.

John is also interested in how histone modification patterns change or are conserved through the cell cycle as the numerous protein complexes required for transcription, DNA replication and repair all bind to and move through chromatin.

Qualifications

  • 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

Biography

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.

Teaching

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

Postgraduate supervision

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

Research

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.

Publications

Halsall JA & Turner BM (2016) An evolutionary perspective explains resistance to histone deacetylase inhibitors in normal cells and cancer. Bioessays. 38(11):1102-1110

Wiersma M, Bussiere M, Halsall JA, Turan N, Slany R, Turner BM & Nightingale KP (2016) Protein kinase Msk1 is a component of the MLL1/KMT2A methyltransferase complex and is essential for regulation of multiple target genes. Epigenetics Chromatin. 9:52

Halsall JA, Turan N, Wiersma M, Turner BM (2015) Cells adapt to the epigenomic disruption caused by histone deacetylase inhibitors through a coordinated, chromatin-mediated transcriptional response. Epigenetics Chromatin. 16(8):29

Terrenoire E, Halsall JA, Turner BM (2015) Immunolabelling of human metaphase chromosomes reveals the same banded distribution of histone H3 isoforms methylated at lysine 4 in primary lymphocytes and cultured cells. BMC Genetics. 16(1):44

Boudadi E, Stower H, Halsall JA, Rutledge CE, Leeb M, Wutz A, O'Neill LP, Nightingale KP, Turner BM (2013) The histone deacetylase inhibitor sodium valproate causes limited transcriptional change in mouse embryonic stem cells but selectively overrides Polycomb-mediated Hoxb silencing. Epigenetics Chromatin. 6(1):11

Halsall JA, Gupta V, O’Neill LP, Turner BM, Nightingale KP (2012) Genes are often sheltered from the global histone hyperacetylation induced by HDAC inhibitors. PLoS One. 7(3):e33453

LinH, Halsall JA, Antczak P, O’Neill LP, Falciani F, Turner BM (2011) Relative over-expression of X-linked genes in mouse embryonic stem cells is consistent with Ohno’s hypothesis. Nat Genet. 43(12):1169-70

Terrenoire E, McRonald F, Halsall JA, Page P, Illingworth RS, Taylor AM, Davison V, O'Neill LP, Turner BM (2010) Immunostaining of modified histones defines high-level features of the human metaphase epigenome. Genome Biol. 11:R110

Halsall JA, Osborne JE, Epstein MP, Pringle JH, Hutchinson PE. (2009) The unfavorable effect of the A allele of the vitamin D receptor promoter polymorphism A-1012G has different mechanisms related to susceptibility and outcome of malignant melanoma. Dermatoendocrinol. 1:54-7

Halsall JA, Osborne JE, Hutchinson PE & Pringle JH (2007) In Silico analysis of the 5′ Region of the Vitamin D receptor gene: Functional implications of evolutionary conservation. J Steroid Biochem Mol Biol. 103:352-6

Halsall JA, Osborne JE, Pringle JH & Hutchinson PE (2005) Vitamin D Receptor gene polymorphisms, particularly the novel A-1012G promoter polymorphism, are associated with vitamin D3 responsiveness and non-familial susceptibility in psoriasis. Pharmacogenet Genomics, 15, 349-55

Halsall JA, Osborne JE, Potter L, Pringle JH & Hutchinson PE (2004) A novel polymorphism in the 1A promoter region of the vitamin D receptor is associated with altered susceptibility and prognosis in malignant melanoma. Br J Cancer, 91: 765-70

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