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IL-10 transcription is negatively regulated by BAF180, a component of the SWI/SNF chromatin remodeling enzyme.

Wurster AL, Precht P, Becker KG, Wood WH, Zhang Y, Wang Z, Pazin MJ - BMC Immunol. (2012)

Bottom Line: We find that T cell development in the thymus and lymphoid periphery is largely normal when the BAF180 gene is deleted late in thymic development.However, BAF180-deficient Th2 cells express high levels of the immunoregulatory cytokine IL-10.These results demonstrate that BAF180 is a repressor of IL-10 transcription in Th2 cells and suggest that the differential recruitment of different SWI/SNF subtypes can have direct consequences on chromatin structure and gene transcription.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, USA.

ABSTRACT

Background: SWI/SNF chromatin remodeling enzymes play a critical role in the development of T helper lymphocytes, including Th2 cells, and directly program chromatin structure at Th2 cytokine genes. Different versions of SWI/SNF complexes, including BAF and PBAF, have been described based on unique subunit composition. However, the relative role of BAF and PBAF in Th cell function and cytokine expression has not been reported.

Results: Here we examine the role of the PBAF SWI/SNF complex in Th cell development and gene expression using mice deficient for a PBAF-specific component, BAF180. We find that T cell development in the thymus and lymphoid periphery is largely normal when the BAF180 gene is deleted late in thymic development. However, BAF180-deficient Th2 cells express high levels of the immunoregulatory cytokine IL-10. BAF180 binds directly to regulatory elements in the Il-10 locus but is replaced by BAF250 BAF complexes in the absence of BAF180, resulting in increased histone acetylation and CBP recruitment to the IL-10 locus.

Conclusions: These results demonstrate that BAF180 is a repressor of IL-10 transcription in Th2 cells and suggest that the differential recruitment of different SWI/SNF subtypes can have direct consequences on chromatin structure and gene transcription.

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BRG1 Binding at the IL-10/IL-24 Locus in multiple T helper subtypes. ChIP-seq profiles from T helper cells for BRG1, STAT6, STAT4 and STAT5B are shown. BRG1 data are from [47], Stat6 data are from [57] and Stat5 data are from [58]. Resting naïve cells (uNaive), resting Th1, (uTh1), resting Th2 (uTh2), re-stimulated Th1 (Th1s), re-stimulated Th2 (Th2s), re-stimulated Th17 (Th17s) cells are shown. Input is shown as a control. Occupancy range values (y axis) are identical for all graphs to allow direct comparison (minimum tag frequency of 0, maximum tag frequency of 1.14 × 10-5). A scale bar for the × axis (genomic location) is shown. Exons are indicated as vertical bars, gene names are to the left, and arrowheads indicate the direction of transcription. The genomic coordinates represented (MM9 assembly) are chromosome 1, 132,770,000 to 132,950,000.
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Figure 10: BRG1 Binding at the IL-10/IL-24 Locus in multiple T helper subtypes. ChIP-seq profiles from T helper cells for BRG1, STAT6, STAT4 and STAT5B are shown. BRG1 data are from [47], Stat6 data are from [57] and Stat5 data are from [58]. Resting naïve cells (uNaive), resting Th1, (uTh1), resting Th2 (uTh2), re-stimulated Th1 (Th1s), re-stimulated Th2 (Th2s), re-stimulated Th17 (Th17s) cells are shown. Input is shown as a control. Occupancy range values (y axis) are identical for all graphs to allow direct comparison (minimum tag frequency of 0, maximum tag frequency of 1.14 × 10-5). A scale bar for the × axis (genomic location) is shown. Exons are indicated as vertical bars, gene names are to the left, and arrowheads indicate the direction of transcription. The genomic coordinates represented (MM9 assembly) are chromosome 1, 132,770,000 to 132,950,000.

Mentions: IL-10 is part of a multi-gene cluster in mouse and human. A recent report indicated that IL-24 expression is Th2 specific, mediated in part by STAT6 function through the IL-24 promoter [67]. We asked whether there might be functional elements dispersed throughout this locus, as found for the IL4/IL13/IL5 locus; these can be identified through genomic analysis, especially when multiple datasets are combined [4,68]. We found BRG1 binding clustered around the IL-24 and IL-10 genes (Figure 10). There were few if any binding regions in the central 60 kb interval containing the IL-20 and IL-19 genes. In resting and stimulated cell types, BRG1 binding was Th2 specific, and binding was stronger in stimulated cells. Consistent with our previous global analysis and analysis of specific genes, these effects were not absolute; for example, there is substantial BRG1 binding in Th1 cells; it is not clear whether this is the result of combinatorial control, or if these sites can be both positively and negatively acting. STAT6 and STAT5 binding was present at numerous upstream and downstream regions, extending the observation of STAT6 at the IL-24 promoter. The location of statistically significant binding regions for both loci is presented as a table (See Additional file 1) of genomic coordinates and features, organized by factor/condition (By Factor tab) and by genomic coordinate (By site tab). We note that occupancy of the IL-19 -19.8 k and IL-10 +3.2 k sites was detected in cells that do not express these genes under these conditions; perhaps negative regulatory elements lie in these regions. We also note that the IL-10 -25.9 k, IL-10 -9 k, IL-10 +9.5 k, and IL-20 +8.6 k elements are bound by BRG1, STAT6, STAT5A and STAT5B; perhaps these are especially important positive elements. We have confirmed that these elements are DHS in Th2 cells (data not shown).


IL-10 transcription is negatively regulated by BAF180, a component of the SWI/SNF chromatin remodeling enzyme.

Wurster AL, Precht P, Becker KG, Wood WH, Zhang Y, Wang Z, Pazin MJ - BMC Immunol. (2012)

BRG1 Binding at the IL-10/IL-24 Locus in multiple T helper subtypes. ChIP-seq profiles from T helper cells for BRG1, STAT6, STAT4 and STAT5B are shown. BRG1 data are from [47], Stat6 data are from [57] and Stat5 data are from [58]. Resting naïve cells (uNaive), resting Th1, (uTh1), resting Th2 (uTh2), re-stimulated Th1 (Th1s), re-stimulated Th2 (Th2s), re-stimulated Th17 (Th17s) cells are shown. Input is shown as a control. Occupancy range values (y axis) are identical for all graphs to allow direct comparison (minimum tag frequency of 0, maximum tag frequency of 1.14 × 10-5). A scale bar for the × axis (genomic location) is shown. Exons are indicated as vertical bars, gene names are to the left, and arrowheads indicate the direction of transcription. The genomic coordinates represented (MM9 assembly) are chromosome 1, 132,770,000 to 132,950,000.
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Figure 10: BRG1 Binding at the IL-10/IL-24 Locus in multiple T helper subtypes. ChIP-seq profiles from T helper cells for BRG1, STAT6, STAT4 and STAT5B are shown. BRG1 data are from [47], Stat6 data are from [57] and Stat5 data are from [58]. Resting naïve cells (uNaive), resting Th1, (uTh1), resting Th2 (uTh2), re-stimulated Th1 (Th1s), re-stimulated Th2 (Th2s), re-stimulated Th17 (Th17s) cells are shown. Input is shown as a control. Occupancy range values (y axis) are identical for all graphs to allow direct comparison (minimum tag frequency of 0, maximum tag frequency of 1.14 × 10-5). A scale bar for the × axis (genomic location) is shown. Exons are indicated as vertical bars, gene names are to the left, and arrowheads indicate the direction of transcription. The genomic coordinates represented (MM9 assembly) are chromosome 1, 132,770,000 to 132,950,000.
Mentions: IL-10 is part of a multi-gene cluster in mouse and human. A recent report indicated that IL-24 expression is Th2 specific, mediated in part by STAT6 function through the IL-24 promoter [67]. We asked whether there might be functional elements dispersed throughout this locus, as found for the IL4/IL13/IL5 locus; these can be identified through genomic analysis, especially when multiple datasets are combined [4,68]. We found BRG1 binding clustered around the IL-24 and IL-10 genes (Figure 10). There were few if any binding regions in the central 60 kb interval containing the IL-20 and IL-19 genes. In resting and stimulated cell types, BRG1 binding was Th2 specific, and binding was stronger in stimulated cells. Consistent with our previous global analysis and analysis of specific genes, these effects were not absolute; for example, there is substantial BRG1 binding in Th1 cells; it is not clear whether this is the result of combinatorial control, or if these sites can be both positively and negatively acting. STAT6 and STAT5 binding was present at numerous upstream and downstream regions, extending the observation of STAT6 at the IL-24 promoter. The location of statistically significant binding regions for both loci is presented as a table (See Additional file 1) of genomic coordinates and features, organized by factor/condition (By Factor tab) and by genomic coordinate (By site tab). We note that occupancy of the IL-19 -19.8 k and IL-10 +3.2 k sites was detected in cells that do not express these genes under these conditions; perhaps negative regulatory elements lie in these regions. We also note that the IL-10 -25.9 k, IL-10 -9 k, IL-10 +9.5 k, and IL-20 +8.6 k elements are bound by BRG1, STAT6, STAT5A and STAT5B; perhaps these are especially important positive elements. We have confirmed that these elements are DHS in Th2 cells (data not shown).

Bottom Line: We find that T cell development in the thymus and lymphoid periphery is largely normal when the BAF180 gene is deleted late in thymic development.However, BAF180-deficient Th2 cells express high levels of the immunoregulatory cytokine IL-10.These results demonstrate that BAF180 is a repressor of IL-10 transcription in Th2 cells and suggest that the differential recruitment of different SWI/SNF subtypes can have direct consequences on chromatin structure and gene transcription.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Molecular Biology and Immunology, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, USA.

ABSTRACT

Background: SWI/SNF chromatin remodeling enzymes play a critical role in the development of T helper lymphocytes, including Th2 cells, and directly program chromatin structure at Th2 cytokine genes. Different versions of SWI/SNF complexes, including BAF and PBAF, have been described based on unique subunit composition. However, the relative role of BAF and PBAF in Th cell function and cytokine expression has not been reported.

Results: Here we examine the role of the PBAF SWI/SNF complex in Th cell development and gene expression using mice deficient for a PBAF-specific component, BAF180. We find that T cell development in the thymus and lymphoid periphery is largely normal when the BAF180 gene is deleted late in thymic development. However, BAF180-deficient Th2 cells express high levels of the immunoregulatory cytokine IL-10. BAF180 binds directly to regulatory elements in the Il-10 locus but is replaced by BAF250 BAF complexes in the absence of BAF180, resulting in increased histone acetylation and CBP recruitment to the IL-10 locus.

Conclusions: These results demonstrate that BAF180 is a repressor of IL-10 transcription in Th2 cells and suggest that the differential recruitment of different SWI/SNF subtypes can have direct consequences on chromatin structure and gene transcription.

Show MeSH
Related in: MedlinePlus