Flexible Long-Range Loops in the VH Gene Region of the Igh Locus Facilitate the Generation of a Diverse Antibody Repertoire

Medvedovic, Jasna; Ebert, Anja; Tagoh, Hiromi; Tamir, Ido; Schwickert, Tanja A.; Novatchkova, Maria; Sun, Qiong; Veld, Pim J Huis in 't; Guo, Chunguang; Yoon, Hye Suk; Denizot, Yves; Holwerda, Sjoerd J B; Laat, Wouter de; Cogné, Michel; Shi, Yang; Alt, Frederick W.; Busslinger, Meinrad

doi:10.1016/j.immuni.2013.08.011

Cited by 130 publications

(206 citation statements)

References 35 publications

Supporting

Mentioning

190

Contrasting

Unclassified

Order By: Relevance

“…Several key NPC-specific enhancer-gene looping interactions were ablated upon Yy1 knockdown. YY1 is an intriguing architectural protein candidate: (1) it is strongly enriched in genome-wide looping interactions in human cell lines (Rao et al 2014); (2) it is necessary for the formation of specific 3D interactions in B cells (Medvedovic et al 2013); (3) it can connect a long-range interaction in B cells in the absence of its transcriptional activation domain (Mehra et al 2016); and (4) it is required for proper neural development (He et al 2007). Future studies should aim to elucidate YY1's function as an architectural protein in non-neural lineages and determine the extent to which YY1's critical role in looping is due to indirect effects on chromatin activity.…”

Section: Wwwgenomeorgmentioning

confidence: 99%

YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment

et al. 2017

View full text Add to dashboard Cite

CTCF is an architectural protein with a critical role in connecting higher-order chromatin folding in pluripotent stem cells. Recent reports have suggested that CTCF binding is more dynamic during development than previously appreciated. Here, we set out to understand the extent to which shifts in genome-wide CTCF occupancy contribute to the 3D reconfiguration of fine-scale chromatin folding during early neural lineage commitment. Unexpectedly, we observe a sharp decrease in CTCF occupancy during the transition from naï ve/primed pluripotency to multipotent primary neural progenitor cells (NPCs). Many pluripotency gene-enhancer interactions are anchored by CTCF, and its occupancy is lost in parallel with loop decommissioning during differentiation. Conversely, CTCF binding sites in NPCs are largely preexisting in pluripotent stem cells. Only a small number of CTCF sites arise de novo in NPCs. We identify another zinc finger protein, Yin Yang 1 (YY1), at the base of looping interactions between NPC-specific genes and enhancers. Putative NPC-specific enhancers exhibit strong YY1 signal when engaged in 3D contacts and negligible YY1 signal when not in loops. Moreover, siRNA knockdown of Yy1 specifically disrupts interactions between key NPC enhancers and their target genes. YY1-mediated interactions between NPC regulatory elements are often nested within constitutive loops anchored by CTCF. Together, our results support a model in which YY1 acts as an architectural protein to connect developmentally regulated looping interactions; the location of YY1-mediated interactions may be demarcated in development by a preexisting topological framework created by constitutive CTCF-mediated interactions.

show abstract

Section: Wwwgenomeorgmentioning

confidence: 99%

YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment

et al. 2017

View full text Add to dashboard Cite

show abstract

“…The 3C templates of activated B cells and plasmablasts or pro-B cells were prepared by using HindIII as the restriction enzyme as previously described (Medvedovic et al, 2013). DNA (200-400 ng) of individual 3C templates was subjected to quantitative TaqMan PCR analysis (qPCR; Hagège et al, 2007).…”

Section: Retroviral Infectionmentioning

confidence: 99%

Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

Wöhner¹,

Tagoh²,

Bilić³

et al. 2016

J. Cell Biol.

Self Cite

View full text Add to dashboard Cite

1201B cell immunity provides acute and long-term protection of the host against infections through the generation and secretion of high-affinity antibodies that recognize a shear unlimited number of pathogens. This enormous adaptive potential of B cells is brought about by V(D)J recombination of the immunoglobulin heavy chain (Igh) and light chain (Igk and Igl) genes in early B cell development, and by subsequent affinity maturation of the Ig heavy chain in late B cell differentiation (Victora and Nussenzweig, 2012). Somatic hypermutation alters the antigen-binding V H sequences of the Ig heavy-chain, whereas class switch recombination (CSR) exchanges the C H exons to generate Ig isotypes with distinct effector functions (Chaudhuri and Alt, 2004). Whereas the activation-induced deaminase (AID) is an essential regulator of both processes (Muramatsu et al., 2000), somatic hypermutation only takes place in germinal centers (GCs), which are formed upon antigen exposure by the interplay of T follicular helper (Tfh) cells and follicular (FO) B cells in secondary lymphoid organs (Victora and Nussenzweig, 2012). Affinity-based selection in this specialized compartment leads to clonal expansion of B cells expressing high-affinity B cell receptors, which subsequently differentiate to proliferating, antibody-secreting plasmablasts (Victora and Nussenzweig, 2012). Upon migration to specialized bone marrow niches, plasmablasts differentiate into long-lived quiescent plasma cells secreting high amounts of antibodies (Nutt et al., 2015). While many transcription factors are involved in coordinating these B cell responses, we have here studied the role of E-proteins in the regulation of these processes.Basic helix-loop-helix (bHLH) transcription factors can be subdivided into different classes based on biochemical and functional properties (Murre, 2005). Class I bHLH proteins, also known as E-proteins, consist of the three members, E2A (Tcf3), E2-2 (Tcf4), and HEB (Tcf12; Murre, 2005), which bind the E-box (CAN NTG) motif with similar sequence specificity (Fig. S1 A). E-proteins are broadly expressed and heterodimerize with class II bHLH proteins in nonlymphoid cell types. Within the lymphoid system, E-proteins function as homodimers or heterodimers with a different E-protein (Bain et al., 1993;Shen and Kadesch, 1995). E-proteins are thought to mainly function as transcriptional activators, as they interact with the co-activators p300 and CBP (Bradney et al., 2003;Bayly et al., 2004), as well as the promoter recognition factor TFI ID (Chen et al., 2013). The activity of E-proteins is controlled by the inhibitor of DNA binding proteins, which are HLH proteins lacking the basic DNA-binding domain, and are thus capable of sequestering E-proteins into DNA-bindingincompetent heterodimers (Kee, 2009).E-proteins control different aspects of B cell development (Murre, 2005). E2A is required for the commitment of lymphoid progenitors to the B cell lineage (Bain et al.,

show abstract

“…Among 5 0 elements, the intronic Em enhancer is reported as a master control element of V(D)J recombination 3,4 . The IgH 3 0 regulatory region (3 0 RR), that encompasses the four transcriptional enhancers hs3a, hs1,2, hs3b and hs4, controls m transcription in mature B-cells 5 , and is the master element controlling conventional class switch recombination (CSR) 6,7 and somatic hypermutation (SHM) 8 but without role on V(D)J recombination 9,10 . CSR is a cis-deletion or trans-recombination process that allows the C m gene to be replaced in mice with one of the downstream C g3 , C g1 , C g2b , C g2a , C e or C a gene.…”

mentioning

confidence: 99%

Elucidation of IgH 3′ region regulatory role during class switch recombination via germline deletion

et al. 2015

Self Cite

View full text Add to dashboard Cite

In mature B cells, class switch recombination (CSR) replaces the expressed constant Cm gene with a downstream C H gene. How the four transcriptional enhancers of the IgH 3 0 regulatory region (3 0 RR) control CSR remains an open question. We have investigated IgG 1 CSR in 3 0 RR-deficient mice. Here we show that the 3 0 RR enhancers target the S g1 acceptor region (and poorly the S m donor region) by acting on epigenetic marks, germline transcription, paused RNA Pol II recruitment, R loop formation, AID targeting and double-strand break generation. In contrast, location and diversity of S m -S g1 junctions are not affected by deletion of the 3 0 RR enhancers. Thus, the 3 0 RR controls the first steps of CSR by priming the S acceptor region but is not implicated in the choice of the end-joining pathway.

show abstract

Flexible Long-Range Loops in the VH Gene Region of the Igh Locus Facilitate the Generation of a Diverse Antibody Repertoire

Cited by 130 publications

References 35 publications

YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment

YY1 and CTCF orchestrate a 3D chromatin looping switch during early neural lineage commitment

Molecular functions of the transcription factors E2A and E2-2 in controlling germinal center B cell and plasma cell development

Elucidation of IgH 3′ region regulatory role during class switch recombination via germline deletion

Contact Info

Product

Resources

About