Professor Peter Cockerill BSc, PhD

• PhD Biochemistry 1983
• BSc (Hons) Microbiology and Biochemistry 1976

Peter Cockerill qualified with a BSc (Hons) in Microbiology and Biochemistry from the University of Melbourne in 1976. He went on to study for a PhD in Biochemistry at the Institute for Cancer Research in London.

Peter took up a post-doctoral position at the University of Texas in Dallas in 1983 where he defined a new class of genetic elements termed MARs which anchor DNA to the nuclear matrix (Cell 1986). Peter continued this research at the Walter and Eliza Hall Institute in Melbourne before moving to the Hanson centre for Cancer Research in Adelaide in 1990.

At the Hanson Centre Peter began investigating cytokine gene regulation and chromatin structure. This led to the discovery of an inducible enhancer upstream of the human GM-CSF gene which is also the target for immunosuppressant Cyclosporin A (PNAS 1993). Peter was appointed as a professor at the Leeds Institute of Molecular Medicine after moving to Leeds in 2001, where he identified all the additional elements required for the correct regulation of the human IL‑3/GM-CSF locus. These studies also defined the pattern of developmental regulation of the locus during haematopoietic development and T cell maturation. This led to the discovery of a significant new class of regulatory elements that function to maintain epigenetic imprints within genes that exist in a primed state in memory T cells.

Peter moved to Birmingham in 2011 where he runs a joint program of research together with Constanze Bonifer. He has major funding from the BBSRC to study the epigenetic basis of memory T cells, and is a joint holder of a Leukaemia and Lymphoma Research program grant investigating the molecular basis of leukaemia.

Since starting genome-wide analyses of T cells several years ago, he has also identified a memory T cell-specific sub-class of enhancer-like elements that do not directly activate transcription, but prime inducible genes to keep them in a poised state where they can rapidly respond to future immune stimuli.

Peter contributes to Masters courses on immune regulation and on epigenetics and bioinformatics. 

Peter regularly supervises PhD student and  is interested in supervising doctoral research students in the following areas:

• Gene regulation in the immune system
• Mechanisms responsible for myeloid leukaemia

Research approaches used in our laboratory

The central focus of our research is to couple the combined approaches of studying chromosomal structure and epigenetic modifications in parallel with studies of gene regulation so as to understand how genes function and how they are regulated at the level of the nucleus. We begin by studying epigenetic modifications within the nucleus to identify open regions of chromatin bearing activating modifications to histone proteins. These regions represent the active transcriptional enhancers that together account for the transcriptional programs in cells.

In parallel we identify the transcription factors bound to these regions. These patterns tell us how cell identity is established, and how these transcriptional programs are deregulated in diseases such as leukaemia. One tool we employ a lot is to use the enzyme DNase I to map the locations of DNase I Hypersensitive Sites (DHSs) which exist at the accessible regions spanning active enhancer elements. When coupled with genome-wide mRNA analyses, a genome-wide DNase-Seq analysis leads to the identification of all the enhancers directly linked to all the genes expressed in any given cell type. This builds upon decades of research where we used the same tools in single gene studies to establish fundamental principles of gene regulation. These approaches have been successfully applied to the following major research areas:

(1) Defining the epigenetic basis of immunological memory in T cells

We set out to investigate the fundamental basis of acquired immunity by studying the ways in which the genome is re-programmed when T lymphocytes become activated for the first time. We showed that a single cycle of T cell activation leads to extensive epigenetic remodelling of genes which leaves them primed in a poised state to rapidly respond when they become activated for a second time as memory T cells. This mechanism represents the fundamental underlying basis of acquired immunity which allows memory T cells to efficiently combat infections.

At birth, the immune system consists of millions of different clones of naive T cells and B cells that are each capable of recognising different foreign molecules, but normally exist in a dormant non-responsive state. We found that many immune response genes, such as inducible cytokine genes, are very slow to respond in naive T cells. However, when T cells become fully activated, over an extended period of T cell Receptor stimulation, naive T cells undergo a complete transformation to become rapidly dividing and highly active effector T cells. This is what normally happens in response to infections. We demonstrated that genome-wide epigenetic remodelling occurs during blast cell transformation to create thousands of DHSs which are then retained even after effector T cells return to the the dormant state as memory T cells. However, the introduction of these primed DHSs allows memory T cells and effector T cells to respond much faster than naive T cells. We showed that the primed DHSs maintain active regions of chromatin that are closely associated with many of the inducible enhancers that control immune response genes. Simply by making these enhancers more accessible, the primed DHSs directly account for the fact that hundreds of inducible genes can respond rapidly in memory T cells but not in naive T cells. Because these primed DHSs do not normally turn on genes on in the resting state, this helps to ensure that the the genes that T cells use to fight infections are tightly regulated and do not get activated at the wrong time inappropriately. It is when these tight controls break down that the body can suffer from auto-immune and inflammatory diseases. This work was published in EMBO J in 2016.

(2) Defining the gene expression signature and regulatory network in leukaemia

The Cockerill and Bonifer groups have teamed up to perform genome-wide analyses of the gene regulatory networks that get deregulated in leukaemia. This research program involves integrated epigenetic and mRNA analyses, and then links these patterns to the underlying mutations in leukaemia cells. We are currently investigating mechanisms of deregulation linked to mutations in several different transcription factors and signalling molecules.

In one such study, we identified a specific chromatin signature that defines DNA elements that are activated specifically in Acute Myeloid Leukaemia (AML) with FLT3-ITD mutations which trigger constitutive receptor signalling which activates MAPK and the transcription factor AP-1. We observed that this pathway leads to the creation of ~1000 FLT3-ITD-specific DHSs that are highly enriched for AP-1, ETS and RUNX motifs, but not for motifs for STAT transcription factors that are activated instead by the JAK signalling pathway. In this way we showed that the FLT3-ITD mutation triggers AP-1 to redistribute ETS and RUNX family6 transcription factors to ~1000 additional sites where do not normally have access. These DHSs are linked to ~100 genes that get activated and which potentially account for the development of AML. This work was published in Cell Reports in 2015.

(3)  Decoding the regulatory network controlling expression of a cytokine gene locus

In our previous single locus gene regulation studies we created a transgenic mouse model of the intact human IL-3/GM-CSF locus. We showed that these two closely linked genes are regulated independently by distinct enhancers (J.Immunol 2010). Furthermore, we showed that the two genes are separated by a CTCF-dependent transcriptional insulator that allows them to be expressed independently in different tissues (Nucleic Acids Research 2010).

In the course of this research we defined an LCR-like region that is required for correct expression of the IL-3 gene. This encompasses a powerful inducible enhancer that largely accounts for the ability of IL-3-expressing cells such as T cells, mast cells, and myeloid progenitor cells to express IL-3. This locus also encompassed the first examples we identified of priming DHSs which lack classic enhancer activity, but maintain chromatin accessibility. This study was published in J. Immunol. in 2012.