A structural hierarchy mediated by multiple nuclear factors establishes <i>IgH</i> locus conformation

Gerasimova, T. I.; Guo, Cui; Ghosh, Amalendu; Qiu, Xiang; Montefiori, Lindsey E.; Verma-Gaur, Jiyoti; Choi, Nancy M.; Feeney, Ann J.; Sen, Ranjan

doi:10.1101/gad.263871.115

Cited by 32 publications

(51 citation statements)

References 47 publications

(78 reference statements)

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“…CTCF can perform other architectural functions, such as bringing together widely separated DNA sequences during V(D)J (Medvedovic et al 2013;Ebert et al 2015;Gerasimova et al 2015;Lin et al 2015;Narendra et al 2015) and class switch (Birshtein 2012) recombination. One class of CTCF sites that does not fit neatly into this picture has been found in the α-satellite repeats of pericentromeric regions.…”

Section: Other Roles For Ctcfmentioning

confidence: 99%

CTCF: making the right connections

2016

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The role of the zinc finger protein CTCF in organizing the genome within the nucleus is now well established. Widely separated sites on DNA, occupied by both CTCF and the cohesin complex, make physical contacts that create large loop domains. Additional contacts between loci within those domains, often also mediated by CTCF, tend to be favored over contacts between loci in different domains. A large number of studies during the past 2 years have addressed the questions: How are these loops generated? What are the effects of disrupting them? Are there rules governing large-scale genome organization? It now appears that the strongest and evolutionarily most conserved of these CTCF interactions have specific rules for the orientation of the paired CTCF sites, implying the existence of a nonequilibrium mechanism of generation. Recent experiments that invert, delete, or inactivate one of a mating CTCF pair result in major changes in patterns of organization and gene expression in the surrounding regions. What remain to be determined are the detailed molecular mechanisms for re-establishing loop domains and maintaining them after replication and mitosis. As recently published data show, some mechanisms may involve interactions with noncoding RNAs as well as protein cofactors. Many CTCF sites are also involved in other functions such as modulation of RNA splicing and specific regulation of gene expression, and the relationship between these activities and loop formation is another unanswered question that should keep investigators occupied for some time.

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Section: Other Roles For Ctcfmentioning

confidence: 99%

CTCF: making the right connections

2016

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“…For example, during CSR, cohesin complex proteins and mediator complex proteins are dynamically recruited to the IgH locus to ensure long-range interactions and to complete CSR, and their absence disregulates CSR 69,70 . Globally, several proteins are implicated in control of IgH long-range interactions, including Pax5, YY1, EZH2, Ikaros, condensin and the above-mentioned CTCF, cohesin and mediator complexes, at different levels of structural organization 71 . These factors contribute to IgH locus contraction and interactions of regulatory regions, recombination substrates, and proteins during VDJ recombination and CSR, establishing some “recombination factories” prone to RAG or AID mediated recombination (Figure 2, middle).…”

Section: Long-range Interactions and Dna Element Synapsis For Optimalmentioning

confidence: 99%

RNA Exosome and Non-coding RNA-Coupled Mechanisms in AID-Mediated Genomic Alterations

Laffleur

Basu

Lim

2017

Journal of Molecular Biology

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The eukaryotic RNA exosome is a well-conserved protein complex with ribonuclease activity implicated in RNA metabolism. Various families of non-coding RNAs (ncRNAs) have been identified as substrates of the complex, underscoring its role as a ncRNA processing/degradation unit. However, the role of RNA exosome and its RNA processing activity on DNA mutagenesis/alteration events have not been investigated until recently. B lymphocytes use two DNA alteration mechanisms, class switch recombination (CSR) and somatic hypermutation (SHM), to re-engineer their antibody gene expressing loci until a tailored antibody gene for a specific antigen is satisfactorily generated. CSR and SHM require the essential activity of the DNA activation induced cytidine deaminase (AID). Causing collateral damage to the B cell genome during CSR and SHM, AID induces unwanted (and sometimes oncogenic) mutations at numerous non-immunoglobulin gene sequences. Recent studies have revealed that AID’s DNA mutator activity is regulated by the RNA exosome complex, thus providing an example of a mechanism that relates DNA mutagenesis with RNA processing. Here, we review the emergent functions of RNA exosome during CSR, SHM and other chromosomal alterations in B cells, and discuss implications relevant to mechanisms that maintain B cell genomic integrity.

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“…We have hypothesized that this noncoding RNA in the Vh locus is at least partially responsible for locus contraction, because we showed by chromosome conformation capture (3C) that the promoters of the most prominent noncoding RNA within the distal Igh locus, PAIR elements, make direct contact with the region near DJ, presumably within a common transcription factory (16). In addition, 3D-FISH and 3C demonstrate decreased interaction of two sites in the middle and distal parts of the Igh locus with Eμ after YY1 knockdown (17). Therefore, the lack of locus contraction Significance Ying Yang 1 (YY1) is a ubiquitously expressed transcription factor that has been demonstrated to be essential for pro-B-cell development as well as lymphoma.…”

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confidence: 95%

YY1 plays an essential role at all stages of B-cell differentiation

Kleiman

Jia

Loguercio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Ying Yang 1 (YY1) is a ubiquitously expressed transcription factor shown to be essential for pro-B-cell development. However, the role of YY1 in other B-cell populations has never been investigated. Recent bioinformatics analysis data have implicated YY1 in the germinal center (GC) B-cell transcriptional program. In accord with this prediction, we demonstrated that deletion of YY1 by Cγ1-Cre completely prevented differentiation of GC B cells and plasma cells. To determine if YY1 was also required for the differentiation of other B-cell populations, we deleted YY1 with CD19-Cre and found that all peripheral B-cell subsets, including B1 B cells, require YY1 for their differentiation. Transitional 1 (T1) B cells were the most dependent upon YY1, being sensitive to even a half-dosage of YY1 and also to short-term YY1 deletion by tamoxifen-induced Cre. We show that YY1 exerts its effects, in part, by promoting B-cell survival and proliferation. ChIP-sequencing shows that YY1 predominantly binds to promoters, and pathway analysis of the genes that bind YY1 show enrichment in ribosomal functions, mitochondrial functions such as bioenergetics, and functions related to transcription such as mRNA splicing. By RNA-sequencing analysis of differentially expressed genes, we demonstrated that YY1 normally activates genes involved in mitochondrial bioenergetics, whereas it normally down-regulates genes involved in transcription, mRNA splicing, NF-κB signaling pathways, the AP-1 transcription factor network, chromatin remodeling, cytokine signaling pathways, cell adhesion, and cell proliferation. Our results show the crucial role that YY1 plays in regulating broad general processes throughout all stages of B-cell differentiation.YY1 | B lymphocytes | differentiation | mitochondrial bioenergetics | transcription

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A structural hierarchy mediated by multiple nuclear factors establishes IgH locus conformation

Cited by 32 publications

References 47 publications

CTCF: making the right connections

CTCF: making the right connections

RNA Exosome and Non-coding RNA-Coupled Mechanisms in AID-Mediated Genomic Alterations

YY1 plays an essential role at all stages of B-cell differentiation

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