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

Clonally stable Vκ allelic choice instructs Igκ repertoire.
Levin-Klein R, Fraenkel S, Lichtenstein M, Matheson LS, Bartok O, Nevo Y, Kadener S, Corcoran AE, Cedar H, Bergman Y

Although much has been done to understand how rearrangement of the Igκ locus is regulated during B-cell development, little is known about the way the variable (V) segments themselves are selected. Here we show, using B6/Cast hybrid pre-B-cell clones, that a limited number of V segments on each allele is stochastically activated as characterized by the appearance of non-coding RNA and histone modifications. The activation states are clonally distinct, stable across cell division and developmentally important in directing the Ig repertoire upon differentiation. Using a new approach of allelic ATAC-seq, we demonstrate that the Igκ V alleles have differential chromatin accessibility, which may serve as the underlying basis of clonal maintenance at this locus, as well as other instances of monoallelic expression throughout the genome. These findings highlight a new level of immune system regulation that optimizes gene diversity.

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Nature communications, 8, 2041-1723, 15575, 2017

PMID: 28555639

Multi-tissue DNA methylation age predictor in mouse.
Stubbs TM, Bonder MJ, Stark AK, Krueger F, Bolland D, Butcher G, Chandra T, Clark SJ, Corcoran A, Eckersley-Maslin M, Field L, Frising UC, Gilbert C, Guedes J, Hernando-Herraez I, Houseley J, Kemp F, MacQueen A, Okkenhaug K, Rhoades M, Santbergen MJC, Stebegg M, von Meyenn F, Stegle O, Reik W

DNA methylation changes at a discrete set of sites in the human genome are predictive of chronological and biological age. However, it is not known whether these changes are causative or a consequence of an underlying ageing process. It has also not been shown whether this epigenetic clock is unique to humans or conserved in the more experimentally tractable mouse.

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Genome biology, 18, 1474-760X, 68, 2017

PMID: 28399939

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

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Keywords

antibody repertoire
b-lymphocytes
epigenome
gene expression
immune system
immunology
nuclear organisation
vdj recombination

Group Members

Latest Publications

Clonally stable Vκ allelic choice instructs Igκ repertoire.

Levin-Klein R, Fraenkel S, Lichtenstein M

Nature communications
8 2041-1723:15575 (2017)

PMID: 28555639

Multi-tissue DNA methylation age predictor in mouse.

Stubbs TM, Bonder MJ, Stark AK

Genome biology
18 1474-760X:68 (2017)

PMID: 28399939

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