The Igκ3′ Enhancer Is Activated by Gradients of Chromatin Accessibility and Protein Association

McDevit, Daniel C.; Perkins, Leslie; Atchison, Michael L.; Nikolajczyk, Barbara S.

doi:10.4049/jimmunol.174.5.2834

Cited by 22 publications

(29 citation statements)

References 48 publications

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“…Homogeneity of the CD11c Ϫ Mac-1 ϩ population was assessed by flow cytometry. Primary splenic B cells were prepared as described (27). Primary splenic T cells were prepared using the pan-T Macs depletion system according to the manufacturer's protocol.…”

Section: Methodsmentioning

confidence: 99%

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The Interleukin-1β Gene Is Transcribed from a Poised Promoter Architecture in Monocytes

Liang

Zhang

McDevit

et al. 2006

Journal of Biological Chemistry

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Cytokine transcription is usually regulated by transcription factor binding and chromatin remodeling following an inducing signal. By contrast, these data showed the interleukin (IL)-1␤ promoter assembles into a "poised" structure, as evidenced by nuclease accessibility and loss of core histones immediately surrounding the transcription start site. Strikingly, these properties do not change upon transcriptional activation by lipopolysaccharide. Furthermore, association of two key transcriptional activators, PU.1 and C/EBP␤, is robust pre-and post-stimulation indicating the IL-1␤ promoter is packaged into a nontranscribed but poised promoter architecture in cells capable of rapidly inducing IL-1␤. Monocyte stimulation causes recruitment of a third factor, IRF-4, to the IL-1␤ enhancer. PU.1 phosphorylation at a CK2 kinase consensus element is required for this recruitment. We showed that CK2 phosphorylates PU.1, CK2 inhibitors abrogate IL-1␤ induction, and CK2 inducibly associates with the IL-1␤ enhancer. Taken together, these data indicate a novel two-step mechanism for IL-1␤ transcription: 1) formation of a poised chromatin architecture, and 2) phosphorylation of an enhancer-bound factor that recruits other activators. We propose that this poised structure may generally characterize rapidly activated genes.

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Section: Methodsmentioning

confidence: 99%

“…Chromatin Immunoprecipitation (ChIP)-ChIPs were performed as published previously (27,30), using 500,000 human or 10 7 murine cells per antibody. Fold enrichment was calculated by 2 (CtinputϪCtChIP) after quantitative amplification of equivalent picogram amounts of DNA (31).…”

Section: Nuclease Probing Of Chromatin Accessibility Assayed On Southernmentioning

confidence: 99%

The Interleukin-1β Gene Is Transcribed from a Poised Promoter Architecture in Monocytes

Liang

Zhang

McDevit

et al. 2006

Journal of Biological Chemistry

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“…We previously showed that TSA can induce histone H3 acetylation at the 3Ј enhancer (36). If this increase in H3 acetylation plays a role in 3Ј enhancer activity, one would expect H3 acetylation to be greater at the 3Ј enhancer than at other segments of the Ig gene.…”

Section: Tsa Induces H3 Acetylation Preferentially At the 3ј Enhancermentioning

confidence: 99%

“…Previously, we showed that TSA could stimulate histone H3 acetylation at the Ig 3Ј enhancer (36). The 3Ј enhancer is implicated in numerous important functions, including transcription, somatic rearrangement, and somatic mutation (6,(43)(44)(45)(46)(47).…”

Section: Tsa Induces 3ј Enhancer Activity and Pu1 Transactivationmentioning

confidence: 99%

Protein Acetylation Regulates Both PU.1 Transactivation and Igκ 3′ Enhancer Activity

Bai

Srinivasan

Perkins

et al. 2005

The Journal of Immunology

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Igκ gene expression and chromatin structure change during B cell development. At the pre-B cell stage, the locus is relatively hypoacetylated on histone H3, whereas it is hyperacetylated at the plasma cell stage. We find in this study that the histone deacetylase inhibitor, trichostatin A (TSA) stimulated 3′ enhancer activity through the PU.1 binding site. TSA also stimulated PU.1 transactivation potential. PU.1 activity was increased by the coactivator acetyltransferase protein, p300, and p300 physically interacted with PU.1 residues 7–30. PU.1 served as a substrate for p300 and was acetylated on lysine residues 170, 171, 206, and 208. Mutation of PU.1 lysines 170 and 171 did not affect PU.1 DNA binding, but did lower the ability of PU.1 to activate transcription in association with p300. Lysine 170 was acetylated in pre-B cells and plasmacytoma cells, but TSA treatment did not stimulate PU.1 acetylation at this residue arguing that a second mechanism can stimulate 3′ enhancer activity. Using chromatin immunoprecipitation assays we found that TSA caused preferential acetylation of histone H3 at the 3′ enhancer. The relevance of these studies for PU.1 function in transcription and hemopoietic development is discussed.

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“…In contrast, a recent analysis of PU. The PU.1 binding site identified in HS1 is part of a PU.1/IRF composite element, similar to the PU.1 sites within E, E3Ј, and the Ig2-4 enhancers (57,69,73). These sites bind PU.1 which in turn recruits either IRF-4 (Pip) or IRF-8 (ICSBP) to form complexes implicated in regulating Ig locus transcription.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Candidate Regulatory Element within the 5′ Flanking Region of the MouseIghLocus Defined by Pro-B Cell-Specific Hypersensitivity Associated with Binding of PU.1, Pax5, and E2A

Pawlitzky

Angeles

Siegel

et al. 2006

The Journal of Immunology

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The Igh locus is controlled by cis-acting elements, including Eμ and the 3′ IgH regulatory region which flank the C region genes within the well-studied 3′ part of the locus. Although the presence of additional control elements has been postulated to regulate rearrangements of the VH gene array that extends to the 5′ end of the locus, the 5′ border of Igh and its flanking region have not been characterized. To facilitate the analysis of this unexplored region and to identify potential novel control elements, we physically mapped the most D-distal VH segments and scanned 46 kb of the immediate 5′ flanking region for DNase I hypersensitive sites. Our studies revealed a cluster of hypersensitive sites 30 kb upstream of the most 5′ VH gene. Detection of one site, HS1, is restricted to pro-B cell lines and HS1 is accessible to restriction enzyme digestion exclusively in normal pro-B cells, the stage defined by actively rearranging Igh-V loci. Sequence motifs within HS1 for PU.1, Pax5, and E2A bind these proteins in vitro and these factors are recruited to HS1 sequence only in pro-B cells. Transient transfection assays indicate that the Pax5 binding site is required for the repression of transcriptional activity of HS1-containing constructs. Thus, our characterization of the region 5′ of the VH gene cluster demonstrated the presence of a single cluster of DNase I hypersensitive sites within the 5′ flanking region, and identified a candidate Igh regulatory region defined by pro-B cell-specific hypersensitivity and interaction with factors implicated in regulating V(D)J recombination.

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The Igκ3′ Enhancer Is Activated by Gradients of Chromatin Accessibility and Protein Association

Cited by 22 publications

References 48 publications

The Interleukin-1β Gene Is Transcribed from a Poised Promoter Architecture in Monocytes

The Interleukin-1β Gene Is Transcribed from a Poised Promoter Architecture in Monocytes

Protein Acetylation Regulates Both PU.1 Transactivation and Igκ 3′ Enhancer Activity

Identification of a Candidate Regulatory Element within the 5′ Flanking Region of the MouseIghLocus Defined by Pro-B Cell-Specific Hypersensitivity Associated with Binding of PU.1, Pax5, and E2A

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