CTCF mediates long-range chromatin looping and local histone modification in the β-globin locus

Splinter, Erik; Heath, Helen; Kooren, Jurgen; Palstra, Robert-Jan; Klous, Petra; Grosveld, Frank; Galjart, Niels; Laat, Wouter de

doi:10.1101/gad.399506

Cited by 626 publications

(373 citation statements)

References 31 publications

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“…The SensiFAST Probe No-ROX kit (Bioline Reagents Ltd.) was used for qPCR amplification, which was performed with the Bio-Rad CFX Connect Real-Time PCR Detection System using region-specific primers and a corresponding LNA Double-Dye probes with FAM and BHQ1 at the 5′ and 3′ ends, respectively (Table S3). As internal control for the quality of the 3C template, the ubiquitously expressed Ercc3 (XPB) locus was analyzed by qPCR (Splinter et al, 2006). The cross-linking frequencies at the Prdm1 and control Ercc3 loci were calculated by using HindIIIdigested and randomly ligated BAC DNA of these loci as a standard for PCR amplification.…”

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.

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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.,

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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.

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“…The human and mouse b-globin loci are also located inside large chromosomal regions of inactive chromatin and are similarly flanked by CTCF-binding sites [17,18]. These were suspected to form a barrier for incoming heterochromatin, but their deletion did not lead to closing or inactivation of the b-globin locus [12,19]. The application of chromosome conformation capture (3C) technology enabled the demonstration that the b-globin CTCF sites physically interact with each other.…”

Section: Introductionmentioning

confidence: 99%

“…They form large chromatin loops encompassing the b-globin main regulatory element, the locus control region (LCR), and its genes. These loops are erythroid-specific and are formed in erythroid progenitor cells, prior to LCR-mediated high expression of the b-globin genes (figure 1a; [12,20]). It was speculated that the CTCF loops can facilitate subsequent spatial interactions between the LCR and its target genes, but evidence for this is still lacking.…”

Section: Introductionmentioning

confidence: 99%

“…More than most other transcription factors CTCF appears to bind to intergenic sequences, often at a distance from the transcriptional start site (TSS) [11]. CTCF was one of the first proteins demonstrated to mediate chromatin looping between its binding sites [12,13]. Further evidence for its role in the organization of genome structure comes from observations that it frequently binds to boundaries between chromosomal regions that occupy distinct locations in the nucleus, to boundaries between regions with different epigenetic signatures and/or different transcriptional activities, and to boundaries between recently identified topological domains, which are spatially defined chromosomal units within which sequences preferentially interact with each other [14,15].…”

Section: Introductionmentioning

confidence: 99%

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CTCF: the protein, the binding partners, the binding sites and their chromatin loops

Holwerda

Laat

2013

Phil. Trans. R. Soc. B

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191

165

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CTCF has it all. The transcription factor binds to tens of thousands of genomic sites, some tissue-specific, others ultra-conserved. It can act as a transcriptional activator, repressor and insulator, and it can pause transcription. CTCF binds at chromatin domain boundaries, at enhancers and gene promoters, and inside gene bodies. It can attract many other transcription factors to chromatin, including tissue-specific transcriptional activators, repressors, cohesin and RNA polymerase II, and it forms chromatin loops. Yet, or perhaps therefore, CTCF's exact function at a given genomic site is unpredictable. It appears to be determined by the associated transcription factors, by the location of the binding site relative to the transcriptional start site of a gene, and by the site's engagement in chromatin loops with other CTCF-binding sites, enhancers or gene promoters. Here, we will discuss genome-wide features of CTCF binding events, as well as locus-specific functions of this remarkable transcription factor.

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“…As for other CTCF-bound regions [7,24], this bait was shown to participate in looping events with other CTCF-bound regions (see the electronic supplementary material, figure S2). In erythroid cells, the a-globin promoters can be seen to interact with their flanking sequences to a much greater degree with new, specific and strong interactions (figure 2b).…”

Section: Resultsmentioning

confidence: 99%

High-resolution analysis of cis -acting regulatory networks at the α-globin locus

Hughes

Lower

Dunham

et al. 2013

Phil. Trans. R. Soc. B

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We have combined the circular chromosome conformation capture protocol with high-throughput, genome-wide sequence analysis to characterize the cis -acting regulatory network at a single locus. In contrast to methods which identify large interacting regions (10–1000 kb), the 4C approach provides a comprehensive, high-resolution analysis of a specific locus with the aim of defining, in detail, the cis -regulatory elements controlling a single gene or gene cluster. Using the human α-globin locus as a model, we detected all known local and long-range interactions with this gene cluster. In addition, we identified two interactions with genes located 300 kb (NME4) and 625 kb (FAM173a) from the α-globin cluster.

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CTCF mediates long-range chromatin looping and local histone modification in the β-globin locus

Cited by 626 publications

References 31 publications

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

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

CTCF: the protein, the binding partners, the binding sites and their chromatin loops

High-resolution analysis of cis -acting regulatory networks at the α-globin locus

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