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Binding targets of transcription factor E2-2 in human plasmacytoid dendritic cells

ABSTRACT: The interferon-producing plasmacytoid dendritic cells (PDC) share common progenitors with antigen-presenting classical dendritic cells (cDC), yet they possess distinct morphology and molecular features resembling those of lymphocytes. It is unclear whether the unique cell fate of PDC is actively maintained in the steady state. We report that the deletion of transcription factor E2-2 from mature peripheral PDC caused their spontaneous differentiation into cells with cDC properties. This included the loss of PDC markers, increase in MHC class II expression and T cell priming capacity, acquisition of dendritic morphology and induction of cDC signature genes. Genome-wide chromatin immunoprecipitation revealed direct binding of E2-2 to key PDC-specific and lymphoid genes, as well as to certain genes enriched in cDC. Thus, E2-2 actively maintains the cell fate of mature PDC and opposes the “default” cDC fate, in part through direct regulation of lineage-specific gene expression programs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE24740 | GEO | 2010/12/21

SECONDARY ACCESSION(S): PRJNA133601

REPOSITORIES: GEO

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Gene expression profile of mature plasmacytoid dendritic cells (PDC) after the deletion of transcription factor E2-2

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Gene expression profile of mature plasmacytoid dendritic cells (PDC) after the deletion of transcription factor E2-2

Project description:The interferon-producing plasmacytoid dendritic cells (PDC) share common progenitors with antigen-presenting classical dendritic cells (cDC), yet they possess distinct morphology and molecular features resembling those of lymphocytes. It is unclear whether the unique cell fate of PDC is actively maintained in the steady state. We report that the deletion of transcription factor E2-2 from mature peripheral PDC caused their spontaneous differentiation into cells with cDC properties. This included the loss of PDC markers, increase in MHC class II expression and T cell priming capacity, acquisition of dendritic morphology and induction of cDC signature genes. Genome-wide chromatin immunoprecipitation revealed direct binding of E2-2 to key PDC-specific and lymphoid genes, as well as to certain genes enriched in cDC. Thus, E2-2 actively maintains the cell fate of mature PDC and opposes the “default” cDC fate, in part through direct regulation of lineage-specific gene expression programs. Inducible deletion of E2-2 (Tcf4) has been performed by administering tamoxifen to conditional E2-2flox/flox Rosa26-CreER+ mice or to E2-2flox/flox Rosa26-CreER- control littermates. Four or six days later total splenocytes were isolated, pooled from 2-3 mice and PDC (CD11b- B220+ CD11clow Bst2+) were isolated by sorting. Global gene expression profiles of E2-2-deficient (null) and control (Ctrl) PDC were compared using Affymetrix microarrays (GPL1261).

2010-12-21 | E-GEOD-24726 | biostudies-arrayexpress

Binding targets of transcription factor E2-2 in human plasmacytoid dendritic cells

Project description:The interferon-producing plasmacytoid dendritic cells (PDC) share common progenitors with antigen-presenting classical dendritic cells (cDC), yet they possess distinct morphology and molecular features resembling those of lymphocytes. It is unclear whether the unique cell fate of PDC is actively maintained in the steady state. We report that the deletion of transcription factor E2-2 from mature peripheral PDC caused their spontaneous differentiation into cells with cDC properties. This included the loss of PDC markers, increase in MHC class II expression and T cell priming capacity, acquisition of dendritic morphology and induction of cDC signature genes. Genome-wide chromatin immunoprecipitation revealed direct binding of E2-2 to key PDC-specific and lymphoid genes, as well as to certain genes enriched in cDC. Thus, E2-2 actively maintains the cell fate of mature PDC and opposes the “default” cDC fate, in part through direct regulation of lineage-specific gene expression programs. Cells of the human PDC lymphoma line CAL-1 (Maeda et al., Int J Hematol 2005) were crosslinked with formaldehyde, sonicated, and subjected to immunoprecipitation with anti-E2-2 mAb (Bain et al., Mol Cell Biol 1993) or mouse IgG control as described (Cisse et al., Cell 2008). After crosslink reversal, the isolated chromatin was amplified, labeled and hybridized to Human Promoter ChIP-on-chip Microarray Set (Agilent Technologies). Hybridized microarrays were scanned and analyzed using DNA Analytics software (Agilent Technologies).

2010-12-21 | E-GEOD-24740 | biostudies-arrayexpress

Mtg16 regulates E protein activity and lineage specification in dendritic cell development (ChIP-seq)

Project description:E protein transcription factors specify major immune cell lineages including lymphocytes and interferon-producing plasmacytoid dendritic cells (pDCs). Corepressors of the ETO family can bind to and block transactivation by E proteins, but the physiological role of these interactions remained unclear. We report that ETO protein Mtg16 binds chromatin primarily through the pDC-specific E protein E2-2 in human pDCs. Mtg16-deficient mice showed impaired pDC development and functionality, whereas the specification of the classical dendritic cells (cDCs) was enhanced. The deletion of Mtg16 caused aberrant expression of E protein antagonist Id2 in pDCs. Thus, Mtg16 acts as a cofactor of E2-2 to promote pDC differentiation and restrict cDC development, revealing an unexpected positive role of ETO proteins in E protein activity. Analysis of E2-2 and Mtg16 immunoprecipitated chromatin from CAL-1 cell line.

2014-06-13 | E-GEOD-43876 | biostudies-arrayexpress

Mtg16 regulates E protein activity and lineage specification in dendritic cell development (gene expression)

Project description:E protein transcription factors specify major immune cell lineages including lymphocytes and interferon-producing plasmacytoid dendritic cells (pDCs). Corepressors of the ETO family can bind to and block transactivation by E proteins, but the physiological role of these interactions remained unclear. We report that ETO protein Mtg16 binds chromatin primarily through the pDC-specific E protein E2-2 in human pDCs. Mtg16-deficient mice showed impaired pDC development and functionality, whereas the specification of the classical dendritic cells (cDCs) was enhanced. The deletion of Mtg16 caused aberrant expression of E protein antagonist Id2 in pDCs. Thus, Mtg16 acts as a cofactor of E2-2 to promote pDC differentiation and restrict cDC development, revealing an unexpected positive role of ETO proteins in E protein activity. pDC from BM of WT and mtg16-KO mice were negatively selected (lin-CD19, Tcrb, Ter119, NK1.1) and sorted as CD11c+Bst2+ population directly in Trizol. RNA was prepared and deposited for microarray processing.

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Project description:Plasmacytoid and conventional dendritic cells (pDC, and cDC) are generated from distinct lymphoid and myeloid progenitor cells in murine bone marrow. Despite the early separation of pDC and cDC lineages, CD11c+ MHCII-/lo Siglec-H+ CCR9lo pDC-like precursor cells are able to differentiate into both pDC and cDC. Single-cell transcriptomics and high-dimensional flow cytometry combined with cell fate analysis revealed the heterogeneity and commitment of subsets in this compartment. While Ly6D– cells within this fraction were cDC-committed and B220hi Ly6Dhi Zbtb46– cells were immediate precursors of pDCs, B220lo Ly6Dhi Zbtb46– cells still had the potential to generate cDCs in addition to pDCs. Transition to cDCs occurred via an intermediary stage marked by coexpression of Siglec-H, Ly6D and Zbtb46. Type I IFN stimulation limited cDC and promoted pDC output from these precursors, demonstrating their plasticity in response to inflammation. Thus, flexibility to divert to cDCs is retained in the pDC lineage at later differentiation stages.

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Continuous expression of the transcription factor E2-2 maintains the cell fate of mature plasmacytoid dendritic cells

Project description:This SuperSeries is composed of the following subset Series: GSE24726: Gene expression profile of mature plasmacytoid dendritic cells (PDC) after the deletion of transcription factor E2-2 GSE24740: Binding targets of transcription factor E2-2 in human plasmacytoid dendritic cells Refer to individual Series

2010-12-21 | E-GEOD-24785 | biostudies-arrayexpress

Mtg16 regulates E protein activity and lineage specification in dendritic cell development (gene expression)

2014-06-13 | GSE43874 | GEO

Mtg16 regulates E protein activity and lineage specification in dendritic cell development (ChIP-seq)

2014-06-13 | GSE43876 | GEO

Tissue-specific factors differentially regulate the expression of antigen-processing enzymes during dendritic cell ontogeny

Project description:Dendritic cells (DC) form a collection of antigen-presenting cells that are distributed throughout the body. Conventional DC (cDC) which include the cDC1 and cDC2 subsets, and plasmacytoid DC (pDC) constitute the two major ontogenically distinct DC populations. The pDC complete their differentiation in bone-marrow (BM) while the cDC subsets derive from pre-committed bone-marrow (BM) precursors, the pre-cDC, that seed lymphoid and non-lymphoid tissues where they further differentiate into mature cDC1 and cDC2. Within different tissues, cDC express distinct phenotype and function. Notably cDC in the thymus are exquisitely efficient at processing and presenting antigens in the class II pathway, while in the spleen they do so only upon maturation induced by danger signals. To appraise this functional heterogeneity, we examined the regulation of the expression of distinct antigen-processing enzymes during DC ontogeny. We analyzed the expression of cathepsin S (CTSS), cathepsin L (CTSL) and thymus specific serine protease (TSSP), three major antigen-processing enzymes regulating class II presentation in cDC, by DC BM precursors and immature and mature cDC from spleen and thymus. We found that pre-cDC in the BM express relatively high levels of these different proteases. Then, their expression is modulated in a tissue-specific and subset–specific manner with immature and mature thymic cDC expressing overall higher levels than immature splenic cDC. On the other hand, TSSP expression level is selectively down-regulated in spleen pDC while CTSS and CTSL are both increased in thymic and splenic pDC. Hence tissue-specific factors program the expression levels of these different proteases during DC differentiation thus conferring tissue-specific function to the different DC subsets.

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