Michael S. Krangel, PhD

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Professor of Immunology
Chair, Department of Immunology
Department:
Immunology
Address:
318 Jones Bldg
Durham, NC 27710
Office Telephone:
(919) 684-4985
Training:
  • PhD, Harvard University, 1982
Research Interests:
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. 
Representative Publications:
  • Chan, EA; Teng, G; Corbett, E; Choudhury, KR; Bassing, CH; Schatz, DG; Krangel, MS. Peripheral subnuclear positioning suppresses Tcrb recombination and segregates Tcrb alleles from RAG2. Proceedings of the National Academy of Sciences of USA. 2013;110:E4628-E4637.  Abstract
  • Shih, HY; Krangel, MS. Chromatin architecture, CCCTC-binding factor, and V(D)J recombination: managing long-distance relationships at antigen receptor loci. Journal of Immunology. 2013;190:4915-4921.  Abstract
  • Callen, E; Faryabi, RB; Luckey, M; Hao, B; Daniel, JA; Yang, W; Sun, HW; Dressler, G; Peng, W; Chi, H; Ge, K; Krangel, MS; Park, JH; Nussenzweig, A. The DNA damage- and transcription-associated protein paxip1 controls thymocyte development and emigration. Immunity. 2012;37:971-985.  Abstract
  • Callen, E; Faryabi, RB; Luckey, M; Hao, B; Daniel, JA; Yang, W; Sun, HW; Dressler, G; Peng, W; Chi, H; Ge, K; Krangel, MS; Park, JH; Nussenzweig, A. The DNA damage- and transcription-associated protein paxip1 controls thymocyte development and emigration. Immunity. 2012;37:971-985.  Abstract
  • Seitan, VC; Krangel, MS; Merkenschlager, M. Cohesin, CTCF and lymphocyte antigen receptor locus rearrangement. Trends in Immunology. 2012;33:153-159.  Abstract
  • Seitan, VC; Krangel, MS; Merkenschlager, M. Cohesin, CTCF and lymphocyte antigen receptor locus rearrangement. Trends in Immunology. 2012;33:153-159.  Abstract
  • Shih, HY; Verma-Gaur, J; Torkamani, A; Feeney, AJ; Galjart, N; Krangel, MS. Tcra gene recombination is supported by a Tcra enhancer- and CTCF-dependent chromatin hub. Proceedings of the National Academy of Sciences of USA. 2012;109:E3493-E3502.  Abstract
  • Shih, HY; Verma-Gaur, J; Torkamani, A; Feeney, AJ; Galjart, N; Krangel, MS. Tcra gene recombination is supported by a Tcra enhancer- and CTCF-dependent chromatin hub. Proceedings of the National Academy of Sciences of USA. 2012;109:E3493-E3502.  Abstract
  • Carabana, J; Watanabe, A; Hao, B; Krangel, MS. A barrier-type insulator forms a boundary between active and inactive chromatin at the murine TCRß locus. Journal of Immunology. 2011;186:3556-3562.  Abstract
  • Hao, B; Krangel, MS. Long-distance regulation of fetal V(¿) gene segment TRDV4 by the Tcrd enhancer. Journal of Immunology. 2011;187:2484-2491.  Abstract
  • Kondilis-Mangum, HD; Shih, HY; Mahowald, G; Sleckman, BP; Krangel, MS. Regulation of TCRß allelic exclusion by gene segment proximity and accessibility. Journal of Immunology. 2011;187:6374-6381.  Abstract
  • Seitan, VC; Hao, B; Tachibana-Konwalski, K; Lavagnolli, T; Mira-Bontenbal, H; Brown, KE; Teng, G; Carroll, T; Terry, A; Horan, K; Marks, H; Adams, DJ; Schatz, DG; Aragon, L; Fisher, AG; Krangel, MS; Nasmyth, K; Merkenschlager, M. A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation. Nature. 2011;476:467-471.  Abstract
  • Shih, HY; Hao, B; Krangel, MS. Orchestrating T-cell receptor ¿ gene assembly through changes in chromatin structure and organization. Immunologic Research: a selective reference to current research and practice. 2011;49:192-201.  Abstract
  • Shih, HY; Hao, B; Krangel, MS. Orchestrating T-cell receptor ¿ gene assembly through changes in chromatin structure and organization. Immunologic Research: a selective reference to current research and practice. 2011;49:192-201.  Abstract
  • Ji, Y; Little, AJ; Banerjee, JK; Hao, B; Oltz, EM; Krangel, MS; Schatz, DG. Promoters, enhancers, and transcription target RAG1 binding during V(D)J recombination. Journal of Experimental Medicine. 2010;207:2809-2816.  Abstract
  • Kondilis-Mangum, HD; Cobb, RM; Osipovich, O; Srivatsan, S; Oltz, EM; Krangel, MS. Transcription-dependent mobilization of nucleosomes at accessible TCR gene segments in vivo. Journal of Immunology. 2010;184:6970-6977.  Abstract
  • Kondilis-Mangum, HD; Cobb, RM; Osipovich, O; Srivatsan, S; Oltz, EM; Krangel, MS. Transcription-dependent mobilization of nucleosomes at accessible TCR gene segments in vivo. Journal of Immunology. 2010;184:6970-6977.  Abstract
  • Shih, HY; Krangel, MS. Distinct contracted conformations of the Tcra/Tcrd locus during Tcra and Tcrd recombination. Journal of Experimental Medicine. 2010;207:1835-1841.  Abstract
  • Abarrategui, I; Krangel, MS. Germline transcription: a key regulator of accessibility and recombination. Advances in Experimental Medicine and Biology. 2009;650:93-102.  Abstract
  • Krangel, MS. Mechanics of T cell receptor gene rearrangement. Current Opinion in Immunology. 2009;21:133-139.  Abstract
  • Krangel, MS. Mechanics of T cell receptor gene rearrangement. Current Opinion in Immunology. 2009;21:133-139.  Abstract
  • Schlimgen, RJ; Reddy, KL; Singh, H; Krangel, MS. Initiation of allelic exclusion by stochastic interaction of Tcrb alleles with repressive nuclear compartments. Nature Immunology. 2008;9:802-809.  Abstract
  • Abarrategui, I; Krangel, MS. Noncoding transcription controls downstream promoters to regulate T-cell receptor alpha recombination. The EMBO Journal. 2007;26:4380-4390.  Abstract
  • Hawwari, A; Krangel, MS. Role for rearranged variable gene segments in directing secondary T cell receptor alpha recombination. Proceedings of the National Academy of Sciences of USA. 2007;104:903-907.  Abstract
  • Krangel, MS. T cell development: better living through chromatin. Nature Immunology. 2007;8:687-694.  Abstract
  • Krangel, MS. T cell development: better living through chromatin. Nature Immunology. 2007;8:687-694.  Abstract
  • Abarrategui, I; Krangel, MS. Regulation of T cell receptor-alpha gene recombination by transcription. Nature Immunology. 2006;7:1109-1115.  Abstract
  • Jackson, AM; Krangel, MS. Turning T-cell receptor beta recombination on and off: more questions than answers. Immunological Reviews. 2006;209:129-141.  Abstract
  • Jackson, AM; Krangel, MS. Turning T-cell receptor beta recombination on and off: more questions than answers. Immunological Reviews. 2006;209:129-141.  Abstract
  • Hawwari, A; Bock, C; Krangel, MS. Regulation of T cell receptor alpha gene assembly by a complex hierarchy of germline Jalpha promoters. Nature Immunology. 2005;6:481-489.  Abstract
  • Hawwari, A; Bock, C; Krangel, MS. Regulation of T cell receptor alpha gene assembly by a complex hierarchy of germline Jalpha promoters. Nature Immunology. 2005;6:481-489.  Abstract
  • Hawwari, A; Krangel, MS. Regulation of TCR delta and alpha repertoires by local and long-distance control of variable gene segment chromatin structure. Journal of Experimental Medicine. 2005;202:467-472.  Abstract
  • Hawwari, A; Krangel, MS. Regulation of TCR delta and alpha repertoires by local and long-distance control of variable gene segment chromatin structure. Journal of Experimental Medicine. 2005;202:467-472.  Abstract
  • Jackson, A; Kondilis, HD; Khor, B; Sleckman, BP; Krangel, MS. Regulation of T cell receptor beta allelic exclusion at a level beyond accessibility. Nature Immunology. 2005;6:189-197.  Abstract