Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation

Šenigl, Filip; Maman, Yaakov; Dinesh, Ravi; Alinikula, Jukka; Seth, Rashu B.; Pecnová, Ľubomíra; Omer, Arina D.; Rao, Suhas S.P.; Weisz, David; Buerstedde, Jean-Marie; Aiden, E; Casellas, Rafael; Hejnar, Jiřı́; Schatz, David G.

doi:10.1016/j.celrep.2019.11.039

Cited by 39 publications

(55 citation statements)

References 88 publications

(120 reference statements)

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“…The HTS is composed of SHM hotspots that upon mutation of cytidine yield stop codons, and the T2A peptide functions through a ribosome skipping mechanism to separate HTS from GFP and prevent decreases in GFP fluorescence intensity. Following a brief, high dose treatment with blasticidin that removes cells with a silenced reporter, SHM at the vector due to the DIVAC element can be read out as loss of GFP expression by FACS—a finding we have confirmed by sequencing the GFP gene after sorting .…”

Section: Resultsmentioning

confidence: 71%

“…Given AID's proclivity for acting at super-enhancers [33,34], our data predict that off-target loci should be enriched in MEF2B and/or E2A binding. We have recently completed a study identifying regions of the genome that are either susceptible or resistant to AID-mediated mutation despite having similar levels of transcription [62]. As predicted, both E2A and MEF2B binding are significantly enriched in susceptible versus resistant regions of the genome.…”

Section: Discussionmentioning

confidence: 72%

“…Our laboratory has recently developed GFP7 , a lentiviral SHM reporter capable of assaying DIVAC elements in Ramos cells (Fig. 2F), to take advantage of the expanded set of reagents and tools available for use in human cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…Eµ and Eµ mutants were cloned into the GFP7 vector by insertion at a HpaI site immediately upstream of the central polypurine tract. Two‐insert overlapping In‐Fusion reactions were used to create binding site mutants.…”

Section: Methodsmentioning

confidence: 99%

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Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting

et al. 2019

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Secondary diversification of the Ig repertoire occurs through somatic hypermutation (SHM), gene conversion (GCV), and class switch recombination (CSR)—three processes that are initiated by activation‐induced cytidine deaminase (AID). AID targets Ig genes at orders of magnitude higher than the rest of the genome, but the basis for this specificity is poorly understood. We have previously demonstrated that enhancers and enhancer‐like sequences from Ig genes are capable of stimulating SHM of neighboring genes in a capacity distinct from their roles in increasing transcription. Here, we use an in vitro proteomics approach to identify E‐box, MEF2, Ets, and Ikaros transcription factor family members as potential binders of these enhancers. ChIP assays in the hypermutating Ramos B cell line confirmed that many of these factors bound the endogenous Igλ enhancer and/or the IgH intronic enhancer (Eμ) in vivo. Further investigation using SHM reporter assays identified binding sites for E2A and MEF2B in Eμ and demonstrated an association between loss of factor binding and decreases in the SHM stimulating activity of Eμ mutants. Our results provide novel insights into trans‐acting factors that dictate SHM targeting and link their activity to specific DNA binding sites within Ig enhancers.

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Section: Resultsmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting

et al. 2019

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“…It was known from work on immunoglobulin SHM that AID activity was targeted specifically to V region exons in the producing cells by special “diversity activation” (DIVAC) enhancer elements at each IG locus [ 162 ]. It has recently been discovered that these DIVAC enhancers target AID activity to execute SHM at non- IG sites in specific inter-chromosomal TADs in the activated B cell nucleus [ 163 ]. Moving a DIVAC element to a TAD where SHM does not normally occur activates AID in that TAD.…”

Section: The Importance Of Cell Type or Virus Infection History Inmentioning

confidence: 99%

How Chaotic Is Genome Chaos?

Shapiro

2021

Cancers

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Cancer genomes evolve in a punctuated manner during tumor evolution. Abrupt genome restructuring at key steps in this evolution has been called “genome chaos.” To answer whether widespread genome change is truly chaotic, this review (i) summarizes the limited number of cell and molecular systems that execute genome restructuring, (ii) describes the characteristic signatures of DNA changes that result from activity of those systems, and (iii) examines two cases where genome restructuring is determined to a significant degree by cell type or viral infection. The conclusion is that many restructured cancer genomes display sufficiently unchaotic signatures to identify the cellular systems responsible for major oncogenic transitions, thereby identifying possible targets for therapies to inhibit tumor progression to greater aggressiveness.

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Differential expression and regulation of MS4A family members in myeloid cells in physiological and pathological conditions

Silva-Gomes

Mapelli

Boutet

et al. 2021

Journal of Leukocyte Biology

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The MS4A gene family encodes 18 tetraspanin-like proteins, most of which with unknown function. MS4A1 (CD20), MS4A2 (FcεRIβ), MS4A3 (HTm4), and MS4A4A play important roles in immunity, whereas expression and function of other members of the family are unknown. The present investigation was designed to obtain an expression fingerprint of MS4A family members, using bioinformatics analysis of public databases, RT-PCR, and protein analysis when possible. MS4A3, MS4A4A, MS4A4E, MS4A6A, MS4A7, and MS4A14 were expressed by myeloid cells. MS4A6A and MS4A14 were expressed in circulating monocytes and decreased during monocyte-to-Mϕ

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Topologically Associated Domains Delineate Susceptibility to Somatic Hypermutation

Cited by 39 publications

References 88 publications

Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting

Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting

How Chaotic Is Genome Chaos?

Differential expression and regulation of MS4A family members in myeloid cells in physiological and pathological conditions

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