Chromatin and Gene Expression

NucleosomeGroup Leaders:          Professor Bryan Turner

                                       Dr John Halsall

Overview

The nucleosome is the basic unit of DNA packaging, formed when DNA is wound tightly around a complex of histone proteins. Beyond packaging, the nucleosome is also a sophisticated signalling module; chemical modifications of the histone proteins, mediated by families of enzymes, produce binding sites for chromatin-interacting proteins. In turn, these chromatin-bound proteins regulate access to DNA for complexes involved in gene expression, DNA repair, replication and other genomic processes.  In this way, the enzyme-catalysed modification of nucleosomal histones underpins a range of fundamental epigenetic processes.

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

Our Research Group

Bryan Turner established the Chromatin and Gene Expression Group in Birmingham in the 1980s. At this time it was known that histone proteins could be post-translationally modified by the addition of different chemical groups, but techniques by which the functions of these modifications could be studied in biological material were not available. Using synthetic peptides incorporating acetylated lysine at selected positions, the group were able to raise antisera specific for histones modified at particular positions. Using these novel reagents, the group showed that acetylation of histone proteins at specific positions was associated with changes in gene expression. This was a ground-breaking discovery. Collaborative projects over the following years confirmed and extended the original findings and antibodies specific for various modified histones are now indispensable reagents for epigenetic research. In 1993 Bryan proposed that histone modifications usually work by acting as receptors for binding proteins.  The identification of multiple reader proteins which specifically recognise modified histone has since shown this to be true and the “histone code” concept, along with antibodies that allow its experimental testing, has driven the rapid growth of the epigenetics field. 

metaphase chromosomes

Metaphase chromosomes immunostained  to detect histone H4 mono-methylated at lysine 4 (green, left panel). X and Y chromosomes (identified with DNA probes, right) are depleted in this modification. 

Today, the role of histone modifications in cellular processes remains the focus of the Chromatin and Gene Expression Group. We have a particular interest in the ways in which environmental agents, including therapeutic drugs and dietary components, can trigger epigenetic change, and in identifying circumstances in which such changes can be heritable, through the cell cycle, from one cell generation to the next.

Current Projects

Sensitivity and Resistance to Epigenetic Drugs

Drugs that inhibit a family of enzymes known as histone deacetylases (HDACs) are undergoing clinical trials against a variety of cancers. While they have been found to be remarkably effective against a few rare cancers, they are much less effective against the most common cancers.

We have identified a resistance mechanism which allows cells to survive HDAC inhibitor (HDACi) treatment.  Using HDACi-sensitive and resistant Burkitt’s lymphoma cell lines as a model system, we are looking to identify those elements of the HDACi response which are essential for resistance.

Several HDACi in clinical use are based on natural products made by bacteria to kill competing micro-organisms. We are testing the hypothesis, based on our data, that resistance to HDAC inhibitors in both normal cells and most cancers, is due to an ancient, evolutionarily conserved defence mechanism that serves to protect the cell’s carefully regulated patterns of gene expression from the disruptive effects of environmental enzyme inhibitors. Understanding how this defence mechanism works will point the way to treatments that can make tumour cells more sensitive to HDAC inhibitor treatment.

Stability and Dynamics of Histone Modifications through the Cell Cycle

When the cell divides (ie. at mitosis) the chromosomes become highly compacted and can be seen with a light microscope. Staining these chromosomes with antibodies to histone modifications demonstrate striking patterns. But what happens to these patterns at other points in the cells cycle?

It is assumed that histone modification patterns are faithfully reproduced during DNA replication, with relatively little experimental evidence. 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.

Comparison of Metaphase Chromosomes

A comparison of metaphase chromosomes (M) stained with antibody to acetylated Histone H3 lysine 9 and ChIP-seq data for H3K9ac in G1 and G2M sorted cells

Recent Publications

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

Halsall JA, Turan N, 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.

Brockdorff N, Turner BM (2015) Dosage compensation in mammals. Cold Spring Harb Perspect Biol. 2:a019406

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. 16:44

Turner BM (2014) Nucleosome signalling; an evolving concept. Biochim Biophys Acta. 1839:623-6

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

Campbell MJ, Turner BM (2013) Altered histone modifications in cancer. Adv Exp Med Biol. 754:81-107

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

Turner BM (2012) The adjustable nucleosome: an epigenetic signaling module.Trends Genet. 28:436-44

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

Staff

Principal Investigators
John Halsall
Bryan Turner