Michael Krangel
George Barth Geller Distinguished Professor of Immunology
Overview
The process of V(D)J recombination assembles T cell receptor (TCR) genes (α,β,γ,δ) from variable (V), diversity (D) and joining (J) gene segments during T cell development, and is essential for the formation of diverse antigen receptor repertoires on αβ and γδ T lymphocytes. We are interested in the molecular basis for developmentally regulated rearrangement and expression of murine TCR genes. One focus of our studies is the TCRα/δ locus, because it represents an intriguing model with two sets of gene segments that are differentially activated for recombination during T cell development. We are also studying the TCRβ locus, because this locus presents a model in which there is a developmental inactivation of V(D)J recombination associated with the process of allelic exclusion. V(D)J recombination depends on the ability of recombinase proteins RAG1 and RAG2 to recognize and generate double-strand breaks at recombination signal sequences that flank TCR gene segments. Our main focus has been on the role of chromatin structure in defining the portions of these loci that are accessible to the RAG recombinase and therefore active for V(D)J recombination, and on the mechanisms by which cis-regulatory elements within these loci (enhancers, promoters) function as developmental regulators of chromatin structure. Our primary approach has been to manipulate cis-acting elements within these loci by gene targeting, and to study the effects of these manipulations on locus chromatin structure and recombination events in developing thymocytes in vivo. An important outcome of this work has been our demonstration that enhancer- and promoter-directed transcription through recombination signal sequences can displace and covalently modify nucleosomes to provide accessibility for RAG binding and V(D)J recombination.
Recent work in our laboratory and elsewhere has highlighted additional properties of antigen receptor loci that likely to play important roles in developmental regulation. One area of interest is subnuclear positioning. We have used three-dimensional fluorescence in situ hybridization (3D-FISH) to show that TCRβ alleles interact stochastically and at high frequency with the nuclear lamina and with foci of pericentromeric heterochromatin, and that these interactions are inhibitory to V(D)J recombination. We suspect that these inhibitory interactions help to promote allelic exclusion by diminishing the likelihood of simultaneous V to DJ recombination on both alleles. Current work is aimed at developing a better understanding of how the TCRβ locus interacts with the nuclear lamina and the mechanism by which this interaction impacts recombination events.
A second area of interest is locus conformation. It is now appreciated that recombination events at antigen receptor loci depend on locus conformational changes that bring into proximity gene segments that may be widely separated in the linear DNA sequence. Conformational states can be defined using 3D-FISH or a chemical crosslinking approach called chromosome conformation capture (3C). Recent studies indicate that developmental changes in locus conformation contribute to allelic exclusion at the TCRβ locus and mediate a transition from TCRδ to TCRα rearrangement at the TCRα/δ locus. Current work aims to address at a molecular level how locus conformational states are maintained and modified during T cell development and how these changes impact long-distance transactions including enhancer-promoter communication and V(D)J recombination.
Positions
George Barth Geller Distinguished Professor of Immunology in the School of Medicine
2020 School of Medicine
Professor of Integrative Immunobiology in the School of Medicine
2003 School of Medicine
Member of the Duke Cancer Institute in the School of Medicine
2012 School of Medicine
Education
Ph.D. 1982
1982 Harvard University
Publications, Grants & Awards
- Grants (16)
- Awards (2)
- Academics Articles (142)
- Book Sections (1)
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
National Institutes of Health
American Association for the Advancement of Science, The
National Institutes of Health
Frontiers in Immunology
Nature Communications
Nucleic Acids Res
J Exp Med
Immunohorizons
Immunohorizons
Frontiers in Immunology
Cell Reports
Immunohorizons
J Immunol
Trends in Genetics : Tig
Nature Communications
Nat Immunol
Proc Natl Acad Sci U S A
Nature Immunology
Molecular and Cellular Biology
Proc Natl Acad Sci U S A
Proc Natl Acad Sci U S A
Immunol Res
Immunol Res
J Exp Med
J Immunol
Curr Opin Immunol
Advances in Experimental Medicine and Biology
The Embo Journal
The Journal of Immunology
Nature Immunology
Proceedings of the National Academy of Sciences of the United States of America
Nature Immunology
The Journal of Immunology
Immunological Reviews
The Journal of Immunology
The Journal of Experimental Medicine
Nature Immunology
The Journal of Immunology
Nature Immunology
The Journal of Immunology
Immunological Reviews
Nature Immunology
The Journal of Immunology
Proceedings of the National Academy of Sciences of the United States of America
Nature Immunology
The Journal of Immunology
The Journal of Experimental Medicine
Clinical Immunology (Orlando, Fla.)
The Journal of Immunology
European Journal of Immunology
Science (New York, N.Y.)
Immunologic Research
Proceedings of the National Academy of Sciences of the United States of America
The Journal of Immunology
The Journal of Immunology
Cold Spring Harbor Symposia on Quantitative Biology
Immunological Reviews
Molecular and Cellular Biology
Molecular and Cellular Biology
Proceedings of the National Academy of Sciences of the United States of America
The Journal of Biological Chemistry
The Journal of Experimental Medicine
European Journal of Immunology
The Journal of Experimental Medicine
The Journal of Experimental Medicine
Molecular and Cellular Biology
Molecular and Cellular Biology
The Journal of Immunology
Molecular Immunology
The Journal of Experimental Medicine
The Journal of Biological Chemistry
The Journal of Experimental Medicine
Molecular and Cellular Biology
Molecular and Cellular Biology
Proceedings of the National Academy of Sciences of the United States of America
Critical Reviews in Immunology
Molecular and Cellular Biology
Current Topics in Microbiology and Immunology
The Journal of Immunology
The Journal of Experimental Medicine
Science (New York, N.Y.)
The Journal of Immunology
The Journal of Immunology
The Journal of Immunology
The Journal of Experimental Medicine
Advances in Experimental Medicine and Biology
Proceedings of the National Academy of Sciences of the United States of America
Science (New York, N.Y.)
Advances in Immunology
Advances in Immunology
Science (New York, N.Y.)
Science (New York, N.Y.)
Human Immunology
Science (New York, N.Y.)
Proceedings of the National Academy of Sciences of the United States of America
The Journal of Experimental Medicine
Nature
The Journal of Experimental Medicine
Immunological Reviews
The Embo Journal
The Journal of Immunology
The Journal of Biological Chemistry
The Journal of Immunology
The Journal of Immunology
The Journal of Immunology
The Journal of Immunology
The Journal of Experimental Medicine
Proceedings of the National Academy of Sciences of the United States of America
Biochemistry
The Journal of Immunology
The Journal of Biological Chemistry
Human Immunology
Scandinavian Journal of Immunology
Molecular Biology of B Cells
Offices & Contact
Durham, NC
27710 Duke Box 3010
Durham, NC
27710