Functional studies of BCL11A: characterization of the conserved BCL11A-XL splice variant and its interaction with BCL6 in nuclear paraspeckles of germinal center B cells

Liu, Hui; Ippolito, Gregory C.; Wall, Jason K.; Niu, Teresa; Probst, Loren; Lee, Baeck Seung; Pulford, Karen; Banham, Alison H.; Stockwin, Luke H.; Shaffer, Arthur L.; Staudt, Louis M.; Das, Chhaya; Dyer, Martin J. S.; Tucker, Philip W.

doi:10.1186/1476-4598-5-18

Cited by 77 publications

(63 citation statements)

References 39 publications

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“…We previously observed that in B cells, exogenous or ectopically overexpressed BCL11A-XL accumulated primarily within nuclear matrix paraspeckles (37). As with those results, we observed localization indistinguishable from that following ectopic delivery of GFP-BCL11A-XL or GFP-BCL11A-XL-K5/A into 293T cells (Fig.…”

Section: Bcl11a-xl Modulates Rag Expressionsupporting

confidence: 69%

“…4B and C and data not shown). This motif defines a superfamily of TFs crucial to the development of several hematopoietic lineages (23,25,37,41,55) (Fig. 1B).…”

Section: Figmentioning

confidence: 99%

“…RAG expression is tightly regulated at both the posttranscriptional and transcriptional levels (2). In addition to the individual promoters for RAG1 and RAG2, the RAG locus contains at least abundantly in hematopoietic lineages (23,37) (Fig. 1B).…”

mentioning

confidence: 99%

“…1B). All isoforms share a conserved N terminus and an atypical C 2 HC Kruppel-like zinc finger, defining a "superfamily" of 5 genes essential to myeloid/lymphoid (EHZF), megakaryocytic (FOG1 and FOG2), T-lymphoid (BCL11B), and B-lymphoid (BCL11A) development (37) (Fig. 1B).…”

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confidence: 99%

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Corrected and Republished from: BCL11A Is a Critical Component of a Transcriptional Network That Activates RAG Expression and V(D)J Recombination

Lee

Iyer

et al. 2018

Molecular and Cellular Biology

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Recombination activating gene 1 (RAG1) and RAG2 are critical enzymes for initiating variable-diversity-joining [V(D)J] segment recombination, an essential process for antigen receptor expression and lymphocyte development. The BCL11A transcription factor is required for B cell and plasmacytoid dendritic cell (pDC) development, but its molecular function(s) in early B cell fate specification and commitment is unknown. We show here that the major B cell isoform, BCL11A-XL, binds directly to the RAG1 promoter as well as directly to regulatory regions of transcription factors previously implicated in both B cell and pDC development to activate RAG1 and RAG2 gene transcription in pro-and pre-B cells. We employed BCL11A overexpression with recombination substrates to demonstrate direct consequences of BCL11A/RAG modulation on V(D)J recombination. We conclude that BCL11A is a critical component of a transcriptional network that regulates B cell fate by controlling V(D)J recombination.KEYWORDS B cell development, Bcl11a, immunology, RAG, V(D)J R ecombination activating gene (RAG) endonuclease catalyzes the cleavage phase of V(D)J recombination (1-4). RAG is encoded by two adjacent genes, RAG1 and RAG2, whose products must interact to form an active endonuclease (5). Both RAG1 and RAG2 are essential for subsequent B and T lymphocyte development (4, 6). In cell-free systems, RAG1 and RAG2 are sufficient to cleave recombination substrates (7,8), but in vivo a number of additional factors are required for chromatin accessibility of V(D)J segments and for appropriate completion of the V(D)J joints (1-3).RAG expression occurs at two distinct points during B cell development. The first phase results in the assembly of the immunoglobulin heavy chain (IgH) in pro-B cells, whereas the second catalyzes Ig light chain (L) assembly in pre-B cells. RAG expression is tightly regulated at both the posttranscriptional and transcriptional levels (2). In addition to the individual promoters for RAG1 and RAG2, the RAG locus contains at least

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Section: Bcl11a-xl Modulates Rag Expressionsupporting

confidence: 69%

“…4B and C and data not shown). This motif defines a superfamily of TFs crucial to the development of several hematopoietic lineages (23,25,37,41,55) (Fig. 1B).…”

Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Corrected and Republished from: BCL11A Is a Critical Component of a Transcriptional Network That Activates RAG Expression and V(D)J Recombination

Lee

Iyer

et al. 2018

Molecular and Cellular Biology

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“…The SNP with the largest effect size is located in the second intron of a gene on chromosome 2, BCL11A. Although BCL11A has been investigated in the context of lymphocyte development (8,9), its role in the red blood cell lineage has not been previously assessed.…”

mentioning

confidence: 99%

Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage-Specific Repressor BCL11A

Sankaran

Menne

et al. 2008

Science

798

671

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Differences in the amount of fetal hemoglobin (HbF) that persists into adulthood affect the severity of sickle cell disease and the β-thalassemia syndromes. Genetic association studies have identified sequence variants in the gene BCL11A that influence HbF levels. Here, we examine BCL11A as a potential regulator of HbF expression. The high-HbF BCL11A genotype is associated with reduced BCL11A expression. Moreover, abundant expression of full-length forms of BCL11A is developmentally restricted to adult erythroid cells. Down-regulation of BCL11A expression in primary adult erythroid cells leads to robust HbF expression. Consistent with a direct role of BCL11A in globin gene regulation, we find that BCL11A occupies several discrete sites in the β-globin gene cluster. BCL11A emerges as a therapeutic target for reactivation of HbF in β-hemoglobin disorders.

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Lipid Deposition Profiles Influence Foreign Body Responses

et al. 2023

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Fibrosis remains a significant cause of failure in implanted biomedical devices and early absorption of proteins on implant surfaces has been shown to be a key instigating factor. However, lipids can also regulate immune activity and their presence may also contribute to biomaterial‐induced foreign body responses (FBR) and fibrosis. Here it is demonstrated that the surface presentation of lipids on implant affects FBR by influencing reactions of immune cells to materials as well as their resultant inflammatory/suppressive polarization. Time‐of‐flight secondary ion mass spectroscopy (ToF‐SIMS) is employed to characterize lipid deposition on implants that are surface‐modified chemically with immunomodulatory small molecules. Multiple immunosuppressive phospholipids (phosphatidylcholine, phosphatidylinositol, phosphatidylethanolamine, and sphingomyelin) are all found to deposit preferentially on implants with anti‐FBR surface modifications in mice. Significantly, a set of 11 fatty acids is enriched on unmodified implanted devices that failed in both mice and humans, highlighting relevance across species. Phospholipid deposition is also found to upregulate the transcription of anti‐inflammatory genes in murine macrophages, while fatty acid deposition stimulated the expression of pro‐inflammatory genes. These results provide further insights into how to improve the design of biomaterials and medical devices to mitigate biomaterial material‐induced FBR and fibrosis.

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Functional studies of BCL11A: characterization of the conserved BCL11A-XL splice variant and its interaction with BCL6 in nuclear paraspeckles of germinal center B cells

Abstract: Background: Chromosomal aberrations of BCL11A at 2p16.1 have been reported in a variety of B-cell malignancies and its deficiency in mice leads to a profound block in B-cell development.

Cited by 77 publications

References 39 publications

Corrected and Republished from: BCL11A Is a Critical Component of a Transcriptional Network That Activates RAG Expression and V(D)J Recombination

Corrected and Republished from: BCL11A Is a Critical Component of a Transcriptional Network That Activates RAG Expression and V(D)J Recombination

Human Fetal Hemoglobin Expression Is Regulated by the Developmental Stage-Specific Repressor BCL11A

Lipid Deposition Profiles Influence Foreign Body Responses

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