Corecruitment of the Grg4 repressor by PU.1 is critical for Pax5‐mediated repression of B‐cell‐specific genes

Linderson, Ylva; Eberhard, Dirk; Malin, Stephen; Johansson, Annica; Busslinger, Meinrad; Pettersson, Sven

doi:10.1038/sj.embor.7400089

Cited by 57 publications

(59 citation statements)

References 24 publications

(37 reference statements)

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“…These results suggest that the methylation status of the promoter region of pTK100-PUx3-Luc is PU.1-and Dnmt3-dependent. p16 gene, a putative target gene controlled by PU.1 There are very few reports indicating that the repression of cell-type-specific gene expression is mediated by PU.1 (Hwang et al, 2004;Linderson et al, 2004). Moreover, there is no report indicating that PU.1-mediated transcriptional repression is mediated by DNA hypermethylation.…”

Section: Resultsmentioning

confidence: 99%

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

et al. 2005

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The Ets transcription factor PU.1 is a hematopoietic master regulator essential for the development of myeloid and B-cell lineages. As we previously reported, PU.1 sometimes represses transcription on forming a complex with mSin3A-histone deacetyl transferase-MeCP2. Here, we show an interaction between PU.1 and DNA methyltransferases, DNA methyltransferase (Dnmt)3a and Dnmt3b (Dnmt3s). Glutathione-S-transferase pulldown assay revealed that PU.1 directly interacted with the ATRX domain of Dnmt3s through the ETS domain. Dnmt3s repressed the transcriptional activity of PU.1 on a reporter construct with trimerized PU.1-binding sites. The repression was recovered by addition of 5-aza-deoxycitidine, a DNA methyltransferase inhibitor, but not trichostatin A, a histone deacetylase inhibitor. Bisulfite sequence analysis revealed that several CpG sites in the promoter region neighboring the PU.1-binding sites were methylated when Dnmt3s were coexpressed with PU.1. We also showed that the CpG sites in the p16 INK4A promoter were methylated by overexpression of PU.1 in NIH3T3 cells, accompanied by a downregulation of p16 INK4A gene expression. These results suggest that PU.1 may downregulate its target genes through an epigenetic modification such as DNA methylation.

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Section: Resultsmentioning

confidence: 99%

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

et al. 2005

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“…Taken together, these results suggest that PU.1 functions as a repressor for the E enhancer. Although much of the literature describes PU.1 as a transcriptional activator, we note that PU.1 was recently found to participate in developmentally regulated repression of several regulatory elements, including the tal-1 silencer, the p16 Ink4a promoter, and the IgH 3Ј regulatory region enhancer HS1,2 (14,62,63).…”

Section: Discussionmentioning

confidence: 99%

“…The factors Ets-1, Elf-1, and PU.1 bind to various sites within the IgH intronic enhancer (10 -12). The 3Ј regulatory region contains binding sites for both Elf-1 and PU.1 (13,14). The Ets transcription factor PU.1 is predicted to be important in B cell development based on two observations.…”

mentioning

confidence: 99%

Spi-C Has Opposing Effects to PU.1 on Gene Expression in Progenitor B Cells

Schweitzer

Huang

Kamath

et al. 2006

The Journal of Immunology

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The Ets transcription factor Spi-C, expressed in B cells and macrophages, is closely related to PU.1 and has the ability to recognize the same DNA consensus sequence. However, the function of Spi-C has yet to be determined. The purpose of this study is to further examine Spi-C activity in B cell development. First, using retroviral vectors to infect PU.1−/− fetal liver progenitors, Spi-C was found to be inefficient at inducing cytokine-dependent proliferation and differentiation of progenitor B (pro-B) cells or macrophages relative to PU.1 or Spi-B. Next, Spi-C was ectopically expressed in fetal liver-derived, IL-7-dependent pro-B cell lines. Wild-type (WT) pro-B cells ectopically expressing Spi-C (WT-Spi-C) have several phenotypic characteristics of pre-B cells such as increased CD25 and decreased c-Kit surface expression. In addition, WT-Spi-C pro-B cells express increased levels of IgH sterile transcripts and reduced levels of expression and transcription of the FcγRIIb gene. Gel-shift analysis suggests that Spi-C, ectopically expressed in pro-B cells, can bind PU.1 consensus sites in the IgH intronic enhancer and FcγRIIb promoter. Transient transfection analysis demonstrated that PU.1 functions to repress the IgH intronic enhancer and activate the FcγRIIb promoter, while Spi-C opposes these activities. WT-Spi-C pro-B cells have reduced levels of dimethylation on lysine 9 of histone H3 within the IgH 3′ regulatory region, indicating that Spi-C can contribute to removal of repressive features in the IgH locus. Overall, these studies suggest that Spi-C may promote B cell differentiation by modulating the activity of PU.1-dependent genes.

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“…Their repressive activity is mediated by Groucho/transducinlike enhancer of split (Gro/TLE) family of transcriptional co-repressors, for example, a transcriptional co-repressor of the family, Grg4, is recruited by Pax5 or Pax3 to suppress B cell-specific genes (46) or the dopachrome tautomerase gene (47), respectively. In addition, Pax2 is shown to recruit Groucho co-repressors (48).…”

Section: Pax6 Expression During Rankl-induced Osteoclastogenesis-mentioning

confidence: 99%

The Paired-box Homeodomain Transcription Factor Pax6 Binds to the Upstream Region of the TRAP Gene Promoter and Suppresses Receptor Activator of NF-κB Ligand (RANKL)-induced Osteoclast Differentiation

Kogawa¹,

Hisatake

Atkins

et al. 2013

Journal of Biological Chemistry

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Background: Negative regulation of osteoclast differentiation is critical for suppression of pathological bone destruction. Results: Pax6 is induced by RANKL in osteoclasts and attenuates osteoclast differentiation via blocking TRAP gene expression. Conclusion: Pax6 functions together with its co-receptor to suppress TRAP gene expression and osteoclastogenesis. Significance: This study provides a new aspect for investigating the molecular targets linked to physiological bone resorption.

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Corecruitment of the Grg4 repressor by PU.1 is critical for Pax5‐mediated repression of B‐cell‐specific genes

Cited by 57 publications

References 24 publications

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

Spi-C Has Opposing Effects to PU.1 on Gene Expression in Progenitor B Cells

The Paired-box Homeodomain Transcription Factor Pax6 Binds to the Upstream Region of the TRAP Gene Promoter and Suppresses Receptor Activator of NF-κB Ligand (RANKL)-induced Osteoclast Differentiation

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