A novel pax5-binding regulatory element in the igκ locus.

Published on May 23, 2014in Frontiers in Immunology4.716
· DOI :10.3389/fimmu.2014.00240
Rena Levin-Klein5
Estimated H-index: 5
(HUJI: Hebrew University of Jerusalem),
Andrei Kirillov5
Estimated H-index: 5
(HUJI: Hebrew University of Jerusalem)
+ 2 AuthorsYehudit Bergman36
Estimated H-index: 36
(HUJI: Hebrew University of Jerusalem)
The Igκ locus undergoes a variety of different molecular processes during B cell development, including V(D)J rearrangement and somatic hypermutations, which are influenced by cis regulatory regions (RR) within the locus. The Igκ locus includes three characterized RRs termed the intronic (iEκ), 3’Eκ and Ed enhancers. We had previously noted that a region of DNA upstream of the iEκ and matrix attachment region (MAR) was necessary for demethylation of the locus in cell culture. In this study, we further characterized this region, which we have termed Dm, for demethylation element. Pre-rearranged Igκ transgenes containing a deletion of the entire Dm region, or of a Pax5 binding site within the region, fail to undergo efficient CpG demethylation in mature B cells in vivo. Furthermore, we generated mice with a deletion of the full Dm region at the endogenous Igκ locus. The most prominent phenotype of these mice is reduced somatic hypermutations in germinal center B cells in Peyer’s patches. In conclusion, we propose the Dm element as a novel Pax5-binding cis regulatory element, which works in concert with the known enhancers, and plays a role in Igκ demethylation and somatic hypermutations.
  • References (61)
  • Citations (5)
📖 Papers frequently viewed together
19 Citations
7 Citations
5 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
#1Hui Chen (UMCG: University Medical Center Groningen)H-Index: 2
#2Hinke G. Kazemier (UMCG: University Medical Center Groningen)H-Index: 10
Last. Marianne G. Rots (UMCG: University Medical Center Groningen)H-Index: 31
view all 6 authors...
Increasing evidence indicates that active DNA demethylation is involved in several processes in mammals, resulting in developmental stage-specificity and cell lineage-specificity. The recently discovered Ten-Eleven Translocation (TET) dioxygenases are accepted to be involved in DNA demethylation by initiating 5-mC oxidation. Aberrant DNA methylation profiles are associated with many diseases. For example in cancer, hypermethylation results in silencing of tumor suppressor genes. Such silenced ge...
100 CitationsSource
#1Junji Otani (Kyoto University)H-Index: 7
#2Hironobu Kimura (Osaka University)H-Index: 10
Last. Shoji Tajima (Osaka University)H-Index: 37
view all 10 authors...
Hydroxymethylcytosine in the genome is reported to be an intermediate of demethylation. In the present study, we demonstrated that maintenance methyltransferase Dnmt1 scarcely catalyzed hemi-hydroxymethylated DNA and that the hemi-hydroxymethylated DNA was not selectively recognized by the SRA domain of Uhrf1, indicating that hydroxymethylcytosine is diluted in a replication-dependent manner. A high level of 5-hydroxymethylcytosine in mouse embryonic stem cells was produced from the methylcytosi...
36 CitationsSource
#1Morgan L. MaederH-Index: 27
#2James AngstmanH-Index: 3
Last. J. Keith Joung (Partners HealthCare)H-Index: 62
view all 13 authors...
A fusion protein comprising a TALE DNA-targeting domain and the 5-methylcytosine hydroxylase TET1 enables investigation of the function of specific DNA methylation events.
314 CitationsSource
#1Annalisa DiRuscio (UCSC: Catholic University of the Sacred Heart)H-Index: 15
#2Alexander K. Ebralidze (Harvard University)H-Index: 19
Last. Daniel G. Tenen (Harvard University)H-Index: 95
view all 18 authors...
Summary DNA methylation was described almost a century ago. However, the rules governing its establishment and maintenance remain elusive. Here, we present data demonstrating that active transcription regulates levels of genomic methylation. We identified a novel RNA arising from the CEBPA gene locus critical in regulating the local DNA methylation profile. This RNA binds to DNMT1 and prevents CEBPA gene locus methylation. Deep sequencing of transcripts associated with DNMT1 combined with genome...
281 CitationsSource
#1Lorenzo de la RicaH-Index: 7
Last. Esteban BallestarH-Index: 49
view all 10 authors...
Background: DNA methylation is a key epigenetic mechanism for driving and stabilizing cell-fate decisions. Local deposition and removal of DNA methylation are tightly coupled with transcription factor binding, although the relationship varies with the specific differentiation process. Conversion of monocytes to osteoclasts is a unique terminal differentiation process within the hematopoietic system. This differentiation model is relevant to autoimmune disease and cancer, and there is abundant kn...
89 CitationsSource
#1Paul GuilhamonH-Index: 10
Last. Stephan Beck (UCL: University College London)H-Index: 81
view all 15 authors...
Cancer-associated mutations in isocitrate dehydrogenase are proposed to impair TET2-dependent DNA demethylation. By comparing the methylomes of IDH-mutant cancers, the authors identify the transcription factor EBF1 as a partner of TET2, suggesting a possible means for targeting TET2 to specific DNA sequences.
94 CitationsSource
#1Maja Klug (DKFZ: German Cancer Research Center)H-Index: 9
#2Sandra SchmidhoferH-Index: 2
Last. Michael RehliH-Index: 38
view all 5 authors...
Background: Cytosine methylation is a frequent epigenetic modification restricting the activity of gene regulatory elements. Whereas DNA methylation patterns are generally inherited during replication, both embryonic and somatic differentiation processes require the removal of cytosine methylation at specific gene loci to activate lineage-restricted elements. However, the exact mechanisms facilitating the erasure of DNA methylation remain unclear in many cases. Results: We previously established...
45 CitationsSource
#1Marganit FaragoH-Index: 7
#2Chaggai RosenbluhH-Index: 2
Last. Yehudit BergmanH-Index: 36
view all 16 authors...
Immunoglobulin genes are expressed from either the maternal or paternal chromosome; it is now shown that in early haematopoietic stem cells, an individual cell can choose either of the two alleles, but as they develop they become committed to only one.
34 CitationsSource
#1Hideharu Hashimoto (Emory University)H-Index: 18
#2Yiwei Liu (Emory University)H-Index: 17
Last. Xiaodong ChengH-Index: 69
view all 8 authors...
Cytosine residues in mammalian DNA occur in at least three forms, cytosine (C), 5-methylcytosine (M; 5mC) and 5-hydroxymethylcytosine (H; 5hmC). During semi-conservative DNA replication, hemi-methylated (M/C) and hemi-hydroxymethylated (H/C) CpG dinucleotides are transiently generated, where only the parental strand is modified and the daughter strand contains native cytosine. Here, we explore the role of DNA methyltransferases (DNMT) and ten eleven translocation (Tet) proteins in perpetuating t...
269 CitationsSource
#1Xiaorong Zhou (Nantong University)H-Index: 4
#2Yougui Xiang (UTSW: University of Texas Southwestern Medical Center)H-Index: 7
Last. William T. Garrard (UTSW: University of Texas Southwestern Medical Center)H-Index: 28
view all 4 authors...
The mouse Igκ gene locus has three known transcriptional enhancers: an intronic enhancer (Ei), a 3′ enhancer (E3′), and a further downstream enhancer (Ed). We previously discovered, using the chromosome conformation-capture technique, that Ei and E3′ interact with a novel DNA sequence near the 3′ end of the Igκ locus, specifically in B cells. In the present investigation, we examined the function of this far downstream element. The sequence is evolutionarily conserved and exhibits a plasmacytoma...
7 CitationsSource
Cited By5
#1E. Mauricio Barajas-Mora (UCSD: University of California, San Diego)H-Index: 1
#1Barajas-Mora Em (UCSD: University of California, San Diego)H-Index: 1
Last. Ann J. Feeney (Scripps Research Institute)H-Index: 34
view all 2 authors...
ABSTRACTEnhancers are defined as regulatory elements that control transcription in a cell-type and developmental stage-specific manner. They achieve this by physically interacting with their cognat...
2 CitationsSource
Activation-induced cytidine deaminase (AID) is required for the immunoglobulin diversification processes of somatic hypermutation, gene conversion and class-switch recombination. The targeting of AID's deamination activity is thought to be a combination of cis- and trans-acting elements, but has not been fully elucidated. Deletion analysis of putative proximal cis-regulatory motifs, while helpful, fails to identify additive versus cumulative effects, redundancy, and may create new motifs where n...
#1Rena Levin-KleinH-Index: 5
#2Yehudit BergmanH-Index: 36
The immunoglobulin light chain loci (Igκ and Igλ) are recombined via V(D)J recombination at the pre-B cell stage during B cell differentiation. The recombination process is highly regulated on multiple levels to ensure proper timing and locus specificity. In this article, we focus on a number of mechanisms which contribute to the tight control of the rearrangement, focusing on the Igκ locus, which is the primary IgL chain utilized in both mice and humans. We explain how regulation of locus acces...
1 CitationsSource
#1Claudia Ribeiro de Almeida (University of Oxford)H-Index: 11
#2Rudi W. Hendriks (EUR: Erasmus University Rotterdam)H-Index: 49
Last. Ralph StadhoudersH-Index: 19
view all 3 authors...
The Igκ locus, which is spread over 3Mb of genomic DNA and contains >100 variable (V) genes, serves as an important model system to study long-range chromatin interactions. Here, we will discuss how in developing B cells in the bone marrow the accessibility of individual Vκ segments is controlled by many lineage-specific and ubiquitously expressed transcription factors that act on various cis-regulatory elements, including promoters, enhancers, and insulators. This dynamic control furthermore in...
7 CitationsSource
#1Ananda L. Roy (Tufts University)H-Index: 32
#2Robert G. Roeder (Rockefeller University)H-Index: 113
The process of generating differentiated cell types performing specific effector functions from their respective undifferentiated precursors is dictated by extracellular signals, which alter the host cell’s capacity to perform cellular functions. One major mechanism for bringing about such changes is at the level of transcription. Thus, the transcription-related induction of previously silent genes and suppression of active genes in response to extracellular signals can result in the acquisition...
1 CitationsSource
#1Rena Levin-Klein (HUJI: Hebrew University of Jerusalem)H-Index: 5
#2Yehudit Bergman (HUJI: Hebrew University of Jerusalem)H-Index: 36
While most genes in the mammalian genome are transcribed from both parental chromosomes in cells where they are expressed, approximately 10% of genes are expressed monoallelically, so that any given cell will express either the paternal or maternal allele, but not both. The antigen receptor genes in B and T cells are well studied examples of a gene family which is expressed in a monoallelic manner, in a process coined "allelic exclusion". During lymphocyte development, only one allele of each an...
14 CitationsSource