Dr Joan Boyes

Profile

I joined the University of Leeds as a University Research Fellow in November 2004 and became a Lecturer in November 2010 and Associate Professor in 2014.

I obtained my BSc in Biochemistry from the University of Oxford in 1987 and my PhD from the University of Vienna in 1991. I undertook postdoctoral work at the NIH, Bethesda, MD, USA from 1991 to 1997. I then held a Kay Kendall Leukaemia Fellowship, followed by a Lister Fellowship at the Institute of Cancer Research London (1998-2004).

Responsibilities

• Postgraduate Progression Tutor

Research interests

V(D)J Recombination and Genome Instability

V(D)J recombination enables a highly diverse repertoire of immunoglobulin and T cell receptor genes to be generated. However, since the recombination reaction involves the breakage and rejoining of DNA, it is also inherently risky and the price humans pay for having such an effective immune system is genome instability and cancer. We are investigating the mechanism by which V(D)J recombination is regulated and how mistakes in this reaction can lead to oncogene activation.

Regulation of V(D)J recombination

V(D)J recombination generates diversity of the variable exon of immunoglobulin and T cell receptor genes by the stochastic joining of individual V, D and J gene segment. All gene segments with the potential to be recombined are flanked by the same recombination signal sequences (RSSs). Moreover, the same lymphoid-specific proteins, RAG1 and RAG2, recognize these RSSs to initiate recombination in both B and T cells. Despite using the same signal sequences and the same proteins, V(D)J recombination is strictly regulated in a cell-, locus- and stage-specific manner. An important question is how this cell and stage specificity is achieved. The key regulatory step is thought to be the specific disruption of the chromatin packaging at the RSSs.

We are investigating the chromatin changes associated with V(D)J recombination, using the mouse immunoglobulin lambda light chain locus (Ig lambda) as a model. This is the smallest antigen receptor locus with only six functional recombining gene segments. We have identified a critical enhancer that regulates recombination of this locus and notably, this enhancer is bound by only two B-cell specific factors, PU.1 and IRF4.

The Ig lambda locus rearranges primarily in pre-B cells but we showed that increased levels just of IRF4 at the earlier pro-B cell stage are enough to completely activate the Ig lambda locus. Using this system, we showed that even when all the known chromatin changes associated with recombination are present, this is not sufficient to completely trigger recombination. Instead, we find a strong correlation between the level of non-coding transcription and recombination of the light chain loci. We showed further that the transient loss of H2A/H2B dimers from nucleosomes, triggered by ongoing transcription is needed to generate a fully active chromatin structure and the initiation of V(D)J recombination. We propose that by fully opening the chromatin for recombination only transiently, this prevents excessive RAG cutting, which could lead to genome instability.

Current projects aim to further investigate the critical steps in long range locus activation.

Role of recombination by-products in triggering genome instability

During V(D)J recombination, the recombining gene segments are brought together and the intervening DNA is excised. The reactive ends of this excised DNA are joined into a circle, the excised signal circle (ESC), which was thought to be lost during cell division. However, more recent studies have shown that the ESC can be (re-)bound by RAG proteins and re-integrated at RSSs and cryptic RSSs in the genome. Since a number of cryptic RSSs lie next to oncogenes, this can lead to oncogene activation and tumourogenesis. We are investigating the regulation of the re-integration reaction as well as other oncogenic effects of the ESC.

• Inhibiting Replication of Circular DNA: A New Way to Suppress Relapse of Childhood Acute Lymphoblastic Leukaemia?

Qualifications

• PhD, Molecular Biology, 1991, IMP, University of Vienna.
• BA, Biochemistry, 1987, Oxford

Student education

• Faculty Graduate School
• FindaPhD Project details:
  • Project 5566
  • Project 42545

Academic roles:

• PGR Progression Tutor

Committees:

• Member of Graduate School Committee (Progression Tutor (SMCB/Astbury))

Projects

<li><a href="//phd.leeds.ac.uk/project/1916-epigenetics-and-cancer:-determining-how-mistakes-in-v(d)j-recombination-trigger-leukaemias-and-lymphomas">Epigenetics and Cancer: Determining how Mistakes in V(D)J Recombination Trigger Leukaemias and Lymphomas</a></li>