Michael S. Krangel

Journal article J Exp Med · January 7, 2019 Featured Publication Expression of Rag1 and Rag2 is tightly regulated in developing T cells to mediate TCR gene assembly. Here we have investigated the molecular mechanisms governing the assembly and disassembly of a transcriptionally active RAG locus chromatin hub in CD4+CD8+ ... Full text Link to item Cite

Diversification of the TCR β Locus Vβ Repertoire by CTCF.

Journal article Immunohorizons · December 2018 Featured Publication The architectural protein CTCF regulates the conformation and recombination of antigen receptor loci. To study the importance of CTCF in Tcrb locus repertoire formation, we created a conditional knockout mouse line that deletes Ctcf early during thymocyte ... Full text Link to item Cite

A Lamina-Associated Domain Border Governs Nuclear Lamina Interactions, Transcription, and Recombination of the Tcrb Locus.

Journal article Cell Rep · November 13, 2018 Featured Publication Tcrb locus V(D)J recombination is regulated by positioning at the nuclear periphery. Here, we used DamID to profile Tcrb locus interactions with the nuclear lamina at high resolution. We identified a lamina-associated domain (LAD) border composed of severa ... Full text Link to item Cite

Variable Extent of Lineage-Specificity and Developmental Stage-Specificity of Cohesin and CCCTC-Binding Factor Binding Within the Immunoglobulin and T Cell Receptor Loci.

Journal article Front Immunol · 2018 Featured Publication CCCTC-binding factor (CTCF) is largely responsible for the 3D architecture of the genome, in concert with the action of cohesin, through the creation of long-range chromatin loops. Cohesin is hypothesized to be the main driver of these long-range chromatin ... Full text Link to item Cite

Tcrd Rearrangement Redirects a Processive Tcra Recombination Program to Expand the Tcra Repertoire.

Journal article Cell Rep · June 6, 2017 Featured Publication Adaptive immunity depends on diverse T cell receptor repertoires generated by variable, diversity, and joining (V[D]J) recombination. Here, we define the principles by which combinatorial diversity is generated in the murine Tcra repertoire. Tcra and Tcrd ... Full text Link to item Cite

An Ectopic CTCF Binding Element Inhibits Tcrd Rearrangement by Limiting Contact between Vδ and Dδ Gene Segments.

Journal article J Immunol · October 15, 2016 Featured Publication Chromatin looping mediated by the CCCTC binding factor (CTCF) regulates V(D)J recombination at Ag receptor loci. CTCF-mediated looping can influence recombination signal sequence (RSS) accessibility by regulating enhancer activation of germline promoters. ... Full text Link to item Cite

Orientation-specific RAG activity in chromosomal loop domains contributes to Tcrd V(D)J recombination during T cell development.

Journal article J Exp Med · August 22, 2016 Featured Publication T cell antigen receptor δ (Tcrd) variable region exons are assembled by RAG-initiated V(D)J recombination events in developing γδ thymocytes. Here, we use linear amplification-mediated high-throughput genome-wide translocation sequencing (LAM-HTGTS) to map ... Full text Link to item Cite

Yin Yang 1 Promotes Thymocyte Survival by Downregulating p53.

Journal article J Immunol · March 15, 2016 Featured Publication Yin Yang 1 (YY1) is a zinc finger protein that functions as a transcriptional activator or repressor and participates in multiple biological processes, including development and tumorigenesis. To investigate the role of YY1 in developing T cells, we used m ... Full text Link to item Cite

Inactivation of nuclear GSK3β by Ser(389) phosphorylation promotes lymphocyte fitness during DNA double-strand break response.

Journal article Nat Commun · January 29, 2016 Featured Publication Variable, diversity and joining (V(D)J) recombination and immunoglobulin class switch recombination (CSR) are key processes in adaptive immune responses that naturally generate DNA double-strand breaks (DSBs) and trigger a DNA repair response. It is unclea ... Full text Link to item Cite

Beyond Hypothesis: Direct Evidence That V(D)J Recombination Is Regulated by the Accessibility of Chromatin Substrates.

Journal article J Immunol · December 1, 2015 Featured Publication Full text Link to item Cite

A discrete chromatin loop in the mouse Tcra-Tcrd locus shapes the TCRδ and TCRα repertoires.

Journal article Nat Immunol · October 2015 Featured Publication The locus encoding the T cell antigen receptor (TCR) α-chain and δ-chain (Tcra-Tcrd) undergoes recombination of its variable-diversity-joining (V(D)J) segments in CD4(-)CD8(-) double-negative thymocytes and CD4(+)CD8(+) double-positive thymocytes to genera ... Full text Open Access Link to item Cite

An anti-silencer- and SATB1-dependent chromatin hub regulates Rag1 and Rag2 gene expression during thymocyte development.

Journal article J Exp Med · May 4, 2015 Featured Publication Rag1 and Rag2 gene expression in CD4(+)CD8(+) double-positive (DP) thymocytes depends on the activity of a distant anti-silencer element (ASE) that counteracts the activity of an intergenic silencer. However, the mechanistic basis for ASE activity is unkno ... Full text Link to item Cite

T-cell receptor α enhancer is inactivated in αβ T lymphocytes.

Journal article Proc Natl Acad Sci U S A · April 7, 2015 Featured Publication The Tcra enhancer (Eα) is essential for Tcra locus germ-line transcription and primary Vα-to-Jα recombination during thymocyte development. We found that Eα is inhibited late during thymocyte differentiation and in αβ T lymphocytes, indicating that it is n ... Full text Link to item Cite

IL-7 coordinates proliferation, differentiation and Tcra recombination during thymocyte β-selection

Journal article Nature Immunology · March 19, 2015 Featured Publication Signaling via the pre-T cell antigen receptor (pre-TCR) and the receptor Notch1 induces transient self-renewal (β-selection) of TCRβ+ CD4-CD8- double-negative stage 3 (DN3) and DN4 progenitor cells that differentiate into C ... Full text Cite

Specification of Vδ and Vα usage by Tcra/Tcrd locus V gene segment promoters.

Journal article J Immunol · January 15, 2015 Featured Publication The Tcra/Tcrd locus undergoes V-Dδ-Jδ rearrangement in CD4(-)CD8(-) thymocytes to form the TCRδ chain of the γδ TCR and V-Jα rearrangement in CD4(+)CD8(+) thymocytes to form the TCRα-chain of the αβ TCR. Most V segments in the locus participate in V-Jα rea ... Full text Link to item Cite

Lineage-specific compaction of Tcrb requires a chromatin barrier to protect the function of a long-range tethering element.

Journal article J Exp Med · January 12, 2015 Featured Publication Gene regulation relies on dynamic changes in three-dimensional chromatin conformation, which are shaped by composite regulatory and architectural elements. However, mechanisms that govern such conformational switches within chromosomal domains remain unkno ... Full text Link to item Cite

Chromatin Dynamics and the Development of the TCRα and TCRδ Repertoires.

Journal article Adv Immunol · 2015 Featured Publication The adaptive immune system allows vertebrates to orchestrate highly specific responses to a virtually unlimited milieu of antigens. Effective adaptive immune responses depend on the capacity of T and B lymphocytes to generate diverse repertoires of antigen ... Full text Link to item Cite

KAP-1 promotes resection of broken DNA ends not protected by γ-H2AX and 53BP1 in G₁-phase lymphocytes.

Journal article Mol Cell Biol · August 2014 Featured Publication The resection of broken DNA ends is required for DNA double-strand break (DSB) repair by homologous recombination (HR) but can inhibit normal repair by nonhomologous end joining (NHEJ), the main DSB repair pathway in G1-phase cells. Antigen receptor gene a ... Full text Link to item Cite

Peripheral subnuclear positioning suppresses Tcrb recombination and segregates Tcrb alleles from RAG2.

Journal article Proc Natl Acad Sci U S A · November 26, 2013 Featured Publication Allelic exclusion requires that the two alleles at antigen-receptor loci attempt to recombine variable (V), diversity (D), and joining (J) gene segments [V(D)J recombination] asynchronously in nuclei of developing lymphocytes. It previously was shown that ... Full text Link to item Cite

Chromatin architecture, CCCTC-binding factor, and V(D)J recombination: managing long-distance relationships at antigen receptor loci.

Journal article J Immunol · May 15, 2013 Featured Publication The rearrangement of T and B lymphocyte Ag receptor loci occurs within a highly complex chromosomal environment and is orchestrated through complex mechanisms. During the past decade, a large body of literature has highlighted the significance of chromatin ... Full text Link to item Cite

The DNA damage- and transcription-associated protein paxip1 controls thymocyte development and emigration.

Journal article Immunity · December 14, 2012 Featured Publication Histone 3 lysine 4 trimethylation (H3K4me3) is associated with promoters of active genes and found at hot spots for DNA recombination. Here we have shown that PAXIP1 (also known as PTIP), a protein associated with MLL3 and MLL4 methyltransferase and the DN ... Full text Link to item Cite

Tcra gene recombination is supported by a Tcra enhancer- and CTCF-dependent chromatin hub.

Journal article Proc Natl Acad Sci U S A · December 11, 2012 Featured Publication Antigen receptor locus V(D)J recombination requires interactions between widely separated variable (V), diversity (D), and joining (J) gene segments, but the mechanisms that generate these interactions are not well understood. Here we assessed mechanisms t ... Full text Link to item Cite

Cohesin, CTCF and lymphocyte antigen receptor locus rearrangement.

Journal article Trends Immunol · April 2012 Featured Publication The somatic recombination of lymphocyte antigen receptor loci is integral to lymphocyte differentiation and adaptive immunity. Here we review the relation of this highly choreographed process with the zinc finger protein CTCF and with cohesin, a protein co ... Full text Link to item Cite

Regulation of TCRβ allelic exclusion by gene segment proximity and accessibility.

Journal article J Immunol · December 15, 2011 Featured Publication Ag receptor loci are regulated to promote allelic exclusion, but the mechanisms are not well understood. Assembly of a functional TCR β-chain gene triggers feedback inhibition of V(β)-to-DJ(β) recombination in double-positive (DP) thymocytes, which correla ... Full text Link to item Cite

Long-distance regulation of fetal V(δ) gene segment TRDV4 by the Tcrd enhancer.

Journal article J Immunol · September 1, 2011 Featured Publication Murine Tcra and Tcrd gene segments are organized into a single genetic locus (Tcra/Tcrd locus) that undergoes V(D)J recombination in CD4(-)CD8(-) double-negative (DN) thymocytes to assemble Tcrd genes and in CD4(+)CD8(+) double-positive thymocytes to assem ... Full text Link to item Cite

A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation.

Journal article Nature · August 10, 2011 Featured Publication Cohesin enables post-replicative DNA repair and chromosome segregation by holding sister chromatids together from the time of DNA replication in S phase until mitosis. There is growing evidence that cohesin also forms long-range chromosomal cis-interaction ... Full text Link to item Cite

Immunology at Duke: 2011.

Journal article Immunol Res · April 2011 Featured Publication Full text Link to item Cite

Orchestrating T-cell receptor α gene assembly through changes in chromatin structure and organization.

Journal article Immunol Res · April 2011 Featured Publication V(D)J recombination is regulated through changes in chromatin structure that allow recombinase proteins access to recombination signal sequences and through changes in three-dimensional chromatin organization that bring pairs of distant recombination signa ... Full text Link to item Cite

A barrier-type insulator forms a boundary between active and inactive chromatin at the murine TCRβ locus.

Journal article J Immunol · March 15, 2011 Featured Publication In CD4(-)CD8(-) double-negative thymocytes, the murine Tcrb locus is composed of alternating blocks of active and inactive chromatin containing Tcrb gene segments and trypsinogen genes, respectively. Although chromatin structure is appreciated to be critic ... Full text Link to item Cite

Promoters, enhancers, and transcription target RAG1 binding during V(D)J recombination.

Journal article J Exp Med · December 20, 2010 Featured Publication V(D)J recombination assembles antigen receptor genes in a well-defined order during lymphocyte development. This sequential process has long been understood in the context of the accessibility model, which states that V(D)J recombination is regulated by co ... Full text Link to item Cite

Distinct contracted conformations of the Tcra/Tcrd locus during Tcra and Tcrd recombination.

Journal article J Exp Med · August 30, 2010 Featured Publication Studies have suggested that antigen receptor loci adopt contracted conformations to promote long-distance interactions between gene segments during V(D)J recombination. The Tcra/Tcrd locus is unique because it undergoes highly divergent Tcrd and Tcra recom ... Full text Link to item Cite

Transcription-dependent mobilization of nucleosomes at accessible TCR gene segments in vivo.

Journal article J Immunol · June 15, 2010 Featured Publication Accessibility of chromosomal recombination signal sequences to the RAG protein complex is known to be essential for V(D)J recombination at Ag receptor loci in vivo. Previous studies have addressed the roles of cis-acting regulatory elements and germline tr ... Full text Link to item Cite