Loss of Bright/ARID3a Function Promotes Developmental Plasticity

An, Guangyu; Miner, Cathrine A.; Nixon, Jamee C.; Kincade, Paul W.; Bryant, James; Tucker, Philip W.; Webb, Carol F.

doi:10.1002/stem.491

Cited by 42 publications

(43 citation statements)

References 44 publications

(53 reference statements)

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“…We previously showed that ARID3a enhances transcription of a subset of IgH promoters after B cell activation (11–14, 43, 44), and that it can act as a repressor of pluripotency genes, including Oct4, in somatic cells (45, 46). However, the gene targets and mechanisms by which ARID3a functions in HSPCs are unknown.…”

Section: Discussionmentioning

confidence: 99%

Differential Expression of the Transcription Factor ARID3a in Lupus Patient Hematopoietic Progenitor Cells

Ratliff

Ward

Merrill

et al. 2015

The Journal of Immunology

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Although hematopoietic progenitor/stem cells (HPSCs) are used for transplantation, characterization of the multiple subsets within this population in man has lagged behind similar studies in mice. We found that expression of the DNA-binding protein, ARID3a, in mouse stem cells was important for normal development of hematopoietic lineages; however, progenitors expressing ARID3a in man have not been defined. We previously showed increased numbers of ARID3a+ B cells in nearly half of systemic lupus erythematosus (SLE) patients, and that total numbers of ARID3a+ B cells were associated with increased disease severity. Because expression of ARID3a in those SLE patients occurred throughout all B cell subsets, we hypothesized that ARID3a expression in patient HSPCs might also be increased relative to expression in healthy controls. Our data now show that ARID3a expression is not limited to any defined subset of HPSCs in either healthy controls or SLE patients. Numbers of ARID3a+ HSPCs in SLE patients were increased over numbers of ARID3a+ cells in healthy controls. While all SLE-derived HPSCs exhibited poor colony formation in vitro compared to controls, SLE HPSCs with high numbers of ARID3a+ cells yielded increased numbers of cells expressing the early progenitor marker, CD34. SLE HPSCs with high numbers of ARID3a+ cells also more readily generated autoantibody producing cells than HPSCs with lower levels of ARID3a in a humanized mouse model. These data reveal new functions for ARID3a in early hematopoiesis and suggest that knowledge regarding ARID3a levels in HPSCs could be informative for applications requiring transplantation of those cells.

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Section: Discussionmentioning

confidence: 99%

Differential Expression of the Transcription Factor ARID3a in Lupus Patient Hematopoietic Progenitor Cells

Ratliff

Ward

Merrill

et al. 2015

The Journal of Immunology

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“…15,17 Indeed, Bright/ARID3A inhibition causes increased developmental plasticity in mouse and human cells, 15,17 notably by increasing the expression of pluripotency-associated factors such as Oct4, Sox2, Klf4 and Nanog. To evaluate whether repression of ARID3a can induce the transcription of these markers, we tested their expression levels using reverse transcriptase quantitative PCR in B-ALL patients with or without the t (11;14) translocation.…”

Section: Mir-125b Overexpression Induces Proliferation Of Wild-type Pmentioning

confidence: 98%

B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a is a direct target of the oncomir microRNA-125b in progenitor B-cells

et al. 2012

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B-cell acute lymphoblastic leukemia (B-ALL) is often associated with chromosomal translocations leading to the deregulation of proto-oncogenes. MicroRNAs can also be affected by chromosomal alterations and thus contribute to carcinogenesis. The microRNA, miR-125b-1, is overexpressed in B-ALL cases with the t(11;14)(q24;q32) translocation; therefore, we sought to determine the role of this microRNA in B-cell fate. We used murine pre-BI cells alongside murine and human leukemic B-cell lines to show that miR-125b expression enhances proliferation by targeting B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a, an activator of immunoglobulin heavy-chain transcription. Accordingly, this target gene was downregulated in B-ALL patients with the t(11;14)(q24;q32) translocation. Repression of Bright/ARID3a blocked differentiation and conferred a survival advantage to Ba/F3 cells under interleukin-3 starvation. In addition, overexpression of miR-125b protected pre-BI and leukemic B-cell lines from apoptosis by blockade of caspase activation by a mechanism that was independent of p53 and BAK1. In summary, miR-125b can act as an oncogene in B-ALL by targeting ARID3a and mediating its repression, thus leading to a blockage in differentiation, increased proliferation and inhibition of apoptosis.

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“…Chimeras generated by injection of Bright null ES cells had relatively normal numbers and percentages of T cells in thymus and spleen but generally had lower levels of splenic B cells than those resulting from the relatively normal reconstitution achieved by wild-type and Bright heterozygous ES cells (Table). 1 As with the conventional knockout mice, Bright…”

Section: B-1 Cell Generation and Function Is Impaired In Brightmentioning

confidence: 99%

“…Potentially relevant in this regard, Btk can modulate EpoR/c-kit signaling to drive expansion of erythroid progenitors (53). On the other hand, we have recently observed that B cells from both Bright knockout and DN transgenic mice are developmentally plastic (1). Further experiments will be required to more accurately define the mechanism by which Bright deficiency leads to these phenotypic changes.…”

Section: (B) Reconstituted Rag2mentioning

confidence: 99%

The ARID Family Transcription Factor Bright Is Required for both Hematopoietic Stem Cell and B Lineage Development

Webb

Bryant

Popowski

et al. 2011

Molecular and Cellular Biology

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102

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Bright/Arid3a has been characterized both as an activator of immunoglobulin heavy-chain transcription and as a proto-oncogene. Although Bright expression is highly B lineage stage restricted in adult mice, its expression in the earliest identifiable hematopoietic stem cell (HSC) population suggests that Bright might have additional functions. We showed that >99% of Bright ؊/؊ embryos die at midgestation from failed hematopoiesis. Bright ؊/؊ embryonic day 12.5 (E12.5) fetal livers showed an increase in the expression of immature markers. Colony-forming assays indicated that the hematopoietic potential of Bright ؊/؊ mice is markedly reduced. Rare survivors of lethality, which were not compensated by the closely related paralogue Bright-derived protein (Bdp)/Arid3b, suffered HSC deficits in their bone marrow as well as B lineage-intrinsic developmental and functional deficiencies in their peripheries. These include a reduction in a natural antibody, B-1 responses to phosphocholine, and selective T-dependent impairment of IgG1 class switching. Our results place Bright/Arid3a on a select list of transcriptional regulators required to program both HSC and lineage-specific differentiation.The formation and maintenance of blood throughout fetal and adult life rely on the self-renewal of hematopoietic stem cells (HSCs). Rare HSCs arise in the embryonic yolk sac and aorta-gonad mesonephros AGM, seed the fetal liver, and then circulate in the bone marrow of adult mammals. Fetal and adult HSC progenitors become progressively dedicated to differentiation into erythrocytes, myeloid cells, and lymphocytes. Transcription factors critical for the specification and formation of HSCs cover a wide range of DNA binding protein families. An emerging theme is that many of these same regulators are required later for the differentiation of individual blood lineages, which explains why a number of HSC transcription factors were discovered and originally characterized because of their deregulation in hematopoietic malignancies.Bright/Arid3a/Dril1 is the founder of the AT-rich interaction domain (ARID) superfamily of DNA binding proteins (18,60). Bright, in a complex with Bruton's tyrosine kinase (Btk) and TFII-I, binds to specific AT-rich motifs within the nuclearmatrix attachment regions (MARs) of the immunoglobulin heavy-chain (IgH) intronic enhancer (E) and selected IgH promoters to activate IgH transcription (18,25,30,43,44,55,57,58). B cell-specific, transgenic overexpression of Bright leads to partial blocks at both the late-pre-B and T1 immature stages, skewed marginal-zone (MZ) B cell development, increased natural IgM antibody production, and intrinsic autoimmunity (49). Transgenic dominant negative (DN) inhibition of Bright DNA binding results in reduced levels of IgM in serum and functional perturbation of IgM secretion by B-1 cells (39,48). A small pool of Bright cycles from the nucleus into plasma membrane lipid rafts, where it associates with Btk to dampen antigen receptor signaling (48).While highly B lineage restricted in...

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Loss of Bright/ARID3a Function Promotes Developmental Plasticity

Cited by 42 publications

References 44 publications

Differential Expression of the Transcription Factor ARID3a in Lupus Patient Hematopoietic Progenitor Cells

Differential Expression of the Transcription Factor ARID3a in Lupus Patient Hematopoietic Progenitor Cells

B-cell regulator of immunoglobulin heavy-chain transcription (Bright)/ARID3a is a direct target of the oncomir microRNA-125b in progenitor B-cells

The ARID Family Transcription Factor Bright Is Required for both Hematopoietic Stem Cell and B Lineage Development

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