Life Sciences Research for Lifelong Health

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

Comprehensive Cell Surface Protein Profiling Identifies Specific Markers of Human Naive and Primed Pluripotent States.
Collier AJ, Panula SP, Schell JP, Chovanec P, Plaza Reyes A, Petropoulos S, Corcoran AE, Walker R, Douagi I, Lanner F, Rugg-Gunn PJ

Human pluripotent stem cells (PSCs) exist in naive and primed states and provide important models to investigate the earliest stages of human development. Naive cells can be obtained through primed-to-naive resetting, but there are no reliable methods to prospectively isolate unmodified naive cells during this process. Here we report comprehensive profiling of cell surface proteins by flow cytometry in naive and primed human PSCs. Several naive-specific, but not primed-specific, proteins were also expressed by pluripotent cells in the human preimplantation embryo. The upregulation of naive-specific cell surface proteins during primed-to-naive resetting enabled the isolation and characterization of live naive cells and intermediate cell populations. This analysis revealed distinct transcriptional and X chromosome inactivation changes associated with the early and late stages of naive cell formation. Thus, identification of state-specific proteins provides a robust set of molecular markers to define the human PSC state and allows new insights into the molecular events leading to naive cell resetting.

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Cell stem cell, , 1875-9777, , 2017

PMID: 28343983

Two Mutually Exclusive Local Chromatin States Drive Efficient V(D)J Recombination.
Bolland DJ, Koohy H, Wood AL, Matheson LS, Krueger F, Stubbington MJ, Baizan-Edge A, Chovanec P, Stubbs BA, Tabbada K, Andrews SR, Spivakov M, Corcoran AE

Variable (V), diversity (D), and joining (J) (V(D)J) recombination is the first determinant of antigen receptor diversity. Understanding how recombination is regulated requires a comprehensive, unbiased readout of V gene usage. We have developed VDJ sequencing (VDJ-seq), a DNA-based next-generation-sequencing technique that quantitatively profiles recombination products. We reveal a 200-fold range of recombination efficiency among recombining V genes in the primary mouse Igh repertoire. We used machine learning to integrate these data with local chromatin profiles to identify combinatorial patterns of epigenetic features that associate with active VH gene recombination. These features localize downstream of VH genes and are excised by recombination, revealing a class of cis-regulatory element that governs recombination, distinct from expression. We detect two mutually exclusive chromatin signatures at these elements, characterized by CTCF/RAD21 and PAX5/IRF4, which segregate with the evolutionary history of associated VH genes. Thus, local chromatin signatures downstream of VH genes provide an essential layer of regulation that determines recombination efficiency.

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Cell reports, 15, 2211-1247, 2475-87, 2016

PMID: 27264181

RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence.
Galloway A, Saveliev A, Łukasiak S, Hodson DJ, Bolland D, Balmanno K, Ahlfors H, Monzón-Casanova E, Mannurita SC, Bell LS, Andrews S, Díaz-Muñoz MD, Cook SJ, Corcoran A, Turner M

Progression through the stages of lymphocyte development requires coordination of the cell cycle. Such coordination ensures genomic integrity while cells somatically rearrange their antigen receptor genes [in a process called variable-diversity-joining (VDJ) recombination] and, upon successful rearrangement, expands the pools of progenitor lymphocytes. Here we show that in developing B lymphocytes, the RNA-binding proteins (RBPs) ZFP36L1 and ZFP36L2 are critical for maintaining quiescence before precursor B cell receptor (pre-BCR) expression and for reestablishing quiescence after pre-BCR-induced expansion. These RBPs suppress an evolutionarily conserved posttranscriptional regulon consisting of messenger RNAs whose protein products cooperatively promote transition into the S phase of the cell cycle. This mechanism promotes VDJ recombination and effective selection of cells expressing immunoglobulin-μ at the pre-BCR checkpoint.

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Science (New York, N.Y.), 352, 1095-9203, 453-9, 2016

PMID: 27102483

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Keywords

cell biology
immune system
nuclear organisation
vdj recombination

Group Members

Latest Publications

Two Mutually Exclusive Local Chromatin States Drive Efficient V(D)J Recombination.

Bolland DJ, Koohy H, Wood AL

Cell reports
15 2211-1247:2475-87 (2016)

PMID: 27264181

RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence.

Galloway A, Saveliev A, Łukasiak S

Science (New York, N.Y.)
352 1095-9203:453-9 (2016)

PMID: 27102483

Robust 3D DNA FISH using directly labeled probes.

DJ Bolland, MR King, W Reik

Journal of visualized experiments : JoVE
78: (2013)

DOI: 10.3791/50587

PMID: 23978815

Non-coding transcription and large-scale nuclear organisation of immunoglobulin recombination.

MJ Stubbington, AE Corcoran

Current opinion in genetics & development
23 2:81-8 (2013)

DOI: 10.1016/j.gde.2013.01.001

PMID: 23434028

Highly restricted usage of Ig H chain VH14 family gene segments in Slp65-deficient pre-B cell leukemia in mice.

VB Ta, MJ de Bruijn, L Matheson

Journal of immunology (Baltimore, Md. : 1950)
189 10:4842-51 (2012)

DOI: 10.4049/jimmunol.1201440

PMID: 23066158

Editorial overview. Lymphocyte development.

AE Corcoran, AJ Feeney

Current opinion in immunology
24 2:129-31 (2012)

DOI: 10.1016/j.coi.2012.03.003

PMID: 22440337

Local and global epigenetic regulation of V(D)J recombination.

LS Matheson, AE Corcoran

Current topics in microbiology and immunology
356 :65-89 (2012)

DOI: 10.1007/82_2011_137

PMID: 21695632