Anne Corcoran

Research Summary

The focus of our research is understanding the role of chromatin and nuclear organization in controlling gene expression during the development of the immune system.​

​B lymphocytes are cells of the immune system that produce antibodies (immunoglobulins), which recognise and inactivate foreign antigens like bacteria. To cope with the enormous numbers of foreign antigens encountered during our lifespan, these cells must produce millions of different antibodies.

VDJ recombinationRecombination or ‘shuffling' of genes in the immunoglobulin heavy chain (IgH) locus is the first step in generating this huge repertoire.

Special ‘marks’ on the chromatin are thought to underlie the complex choice of gene segments in the multigenic immunoglobulin gene families, that can be recombined during B cell development to produce a large diversity of functional antibody molecules.

Our group studies non-coding RNA transcription (ie generation of transcripts that do not produce protein) in specific parts of the immunoglobulin cluster, which may play a directive role in V(D)J recombination, or mark epigenetic control regions.

Only one of each gene type is used in an individual cell and the resulting DNA sequence encodes a unique IgH, which is expressed with an Ig light chain as a unique highly specific antibody in each cell.

Latest Publications

IL-7R signaling activates widespread V and D gene usage to drive antibody diversity in bone marrow B cells.
Baizan-Edge A, Stubbs BA, Stubbington MJT, Bolland DJ, Tabbada K, Andrews S, Corcoran AE

Generation of the primary antibody repertoire requires V(D)J recombination of hundreds of gene segments in the immunoglobulin heavy chain (Igh) locus. The role of interleukin-7 receptor (IL-7R) signaling in Igh recombination has been difficult to partition from its role in B cell survival and proliferation. With a detailed description of the Igh repertoire in murine IL-7Rα bone marrow B cells, we demonstrate that IL-7R signaling profoundly influences V gene selection during V-to-DJ recombination. We find skewing toward 3' V genes during de novo V-to-DJ recombination more severe than the fetal liver (FL) repertoire and uncover a role for IL-7R signaling in D-to-J recombination. Transcriptome and accessibility analyses suggest reduced expression of B lineage transcription factors (TFs) and targets and loss of D and V antisense transcription in IL-7Rα B cells. Thus, in addition to its roles in survival and proliferation, IL-7R signaling shapes the Igh repertoire by activating underpinning mechanisms.

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Cell reports, 36, 2, 13 Jul 2021

PMID: 34260907

Open Access

Widespread reorganisation of pluripotent factor binding and gene regulatory interactions between human pluripotent states.
Chovanec P, Collier AJ, Krueger C, Várnai C, Semprich CI, Schoenfelder S, Corcoran AE, Rugg-Gunn PJ

The transition from naive to primed pluripotency is accompanied by an extensive reorganisation of transcriptional and epigenetic programmes. However, the role of transcriptional enhancers and three-dimensional chromatin organisation in coordinating these developmental programmes remains incompletely understood. Here, we generate a high-resolution atlas of gene regulatory interactions, chromatin profiles and transcription factor occupancy in naive and primed human pluripotent stem cells, and develop a network-graph approach to examine the atlas at multiple spatial scales. We uncover highly connected promoter hubs that change substantially in interaction frequency and in transcriptional co-regulation between pluripotent states. Small hubs frequently merge to form larger networks in primed cells, often linked by newly-formed Polycomb-associated interactions. We identify widespread state-specific differences in enhancer activity and interactivity that correspond with an extensive reconfiguration of OCT4, SOX2 and NANOG binding and target gene expression. These findings provide multilayered insights into the chromatin-based gene regulatory control of human pluripotent states.

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Nature communications, 12, 1, 07 04 2021

PMID: 33828098

Open Access

Dynamic 3D Locus Organization and Its Drivers Underpin Immunoglobulin Recombination.
Rogers CH, Mielczarek O, Corcoran AE

A functional adaptive immune system must generate enormously diverse antigen receptor (AgR) repertoires from a limited number of AgR genes, using a common mechanism, V(D)J recombination. The AgR loci are among the largest in the genome, and individual genes must overcome huge spatial and temporal challenges to co-localize with optimum variability. Our understanding of the complex mechanisms involved has increased enormously, due in part to new technologies for high resolution mapping of AgR structure and dynamic movement, underpinning mechanisms, and resulting repertoires. This review will examine these advances using the paradigm of the mouse immunoglobulin heavy chain (Igh) locus. We will discuss the key regulatory elements implicated in Igh locus structure. Recent next generation repertoire sequencing methods have shown that local chromatin state at V genes contribute to recombination efficiency. Next on the multidimensional scale, we will describe imaging studies that provided the first picture of the large-scale dynamic looping and contraction the Igh locus undergoes during recombination. We will discuss chromosome conformation capture (3C)-based technologies that have provided higher resolution pictures of Igh locus structure, including the different models that have evolved. We will consider the key transcription factors (PAX5, YY1, E2A, Ikaros), and architectural factors, CTCF and cohesin, that regulate these processes. Lastly, we will discuss a plethora of recent exciting mechanistic findings. These include Rag recombinase scanning for convergent RSS sequences within DNA loops; identification of Igh loop extrusion, and its putative role in Rag scanning; the roles of CTCF, cohesin and cohesin loading factor, WAPL therein; a new phase separation model for Igh locus compartmentalization. We will draw these together and conclude with some horizon-scanning and unresolved questions.

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Frontiers in immunology, 11, 1, 2020

PMID: 33679727

Open Access