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Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation [Hoxb8-FL Brie sgRNA-Seq]

ABSTRACT: The development of all dendritic cells (DCs) including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs) is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected this common Flt3L-driven pathway of DCs differentiation using CRISPR/Cas9-based dropout screening in a Flt3L-dependent progenitor cell line. Genome-wide screening identified multiple regulators of DC differentiation including the glycosylphosphatidylinositol transamidase complex and arginine methyltransferase Carm1, whose role was confirmed in vivo. It also showed that negative regulators of mTOR signaling, including the subunits of TSC and GATOR1 complexes, restricted progenitor growth but enabled DC differentiation, demonstrating that a TSC- and GATOR1-mediated shutdown of mTOR is required for the process. An orthogonal screen focused on transcriptional regulators showed that Trim33 (TIF-1g) is required for DC differentiation. Conditional targeting in vivo revealed an essential role of Trim33 in the development of all DCs, but not of monocytes or granulocytes. In particular, inducible deletion of Trim33 caused a rapid loss of all DC progenitors, pDCs and the cross-presenting cDC1 subset. The loss of Trim33 from DC progenitors caused spontaneous interferon and inflammatory response, aberrant induction of macrophage-specific genes, and failure to induce DC differentiation program. Collectively, these data elucidate common mechanisms that control Flt3L-driven differentiation of the entire DC lineage, and identify Trim33 as its essential regulator.

ORGANISM(S): unidentified plasmid Mus musculus

PROVIDER: GSE202942 | GEO | 2024/04/12

REPOSITORIES: GEO

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Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation [Hoxb8-FL TF sgRNA-Seq]

Project description:The development of all dendritic cells (DCs) including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs) is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected this common Flt3L-driven pathway of DCs differentiation using CRISPR/Cas9-based dropout screening in a Flt3L dependent progenitor cell line. Genome-wide screening identified multiple regulators of DC differentiation including the glycosylphosphatidylinositol transamidase complex and arginine methyltransferase Carm1, whose role was confirmed in vivo. It also showed that negative regulators of mTOR signaling, including the subunits of TSC and GATOR1 complexes, restricted progenitor growth but enabled DC differentiation, demonstrating that a TSC- and GATOR1-mediated shutdown of mTOR is required for the process. An orthogonal screen focused on transcriptional regulators showed that Trim33 (TIF-1g) is required for DC differentiation. Conditional targeting in vivo revealed an essential role of Trim33 in the development of all DCs, but not of monocytes or granulocytes. In particular, inducible deletion of Trim33 caused a rapid loss of all DC progenitors, pDCs and the cross-presenting cDC1 subset. The loss of Trim33 from DC progenitors caused spontaneous interferon and inflammatory response, aberrant induction of macrophage-specific genes, and failure to induce DC differentiation program. Collectively, these data elucidate common mechanisms that control Flt3L-driven differentiation of the entire DC lineage, and identify Trim33 as its essential regulator.

2024-04-12 | GSE259391 | GEO

Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation [Trim33 RNA-Seq]

2024-04-12 | GSE259392 | GEO

Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation [Hoxb8-FL RNA-Seq]

Project description:The development of all dendritic cells (DCs) including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs) is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected this common Flt3L-driven pathway of DCs differentiation using CRISPR/Cas9-based dropout screening in a Flt3L-dependent progenitor cell line. Genome-wide screening identified multiple regulators of DC differentiation including the glycosylphosphatidylinositol transamidase complex and arginine methyltransferase Carm1, whose role was confirmed in vivo. It also showed that negative regulators of mTOR signaling, including the subunits of TSC and GATOR1 complexes, restricted progenitor growth but enabled DC differentiation, demonstrating that a TSC- and GATOR1-mediated shutdown of mTOR is required for the process. An orthogonal screen focused on transcriptional regulators showed that Trim33 (TIF-1g) is required for DC differentiation. Conditional targeting in vivo revealed an essential role of Trim33 in the development of all DCs, but not of monocytes or granulocytes. In particular, inducible deletion of Trim33 caused a rapid loss of all DC progenitors, pDCs and the cross-presenting cDC1 subset. The loss of Trim33 from DC progenitors caused spontaneous interferon and inflammatory response, aberrant induction of macrophage-specific genes, and failure to induce DC differentiation program. Collectively, these data elucidate common mechanisms that control Flt3L-driven differentiation of the entire DC lineage, and identify Trim33 as its essential regulator.

2024-04-12 | GSE202584 | GEO

Genome-wide screening identifies Trim33 as an essential regulator of dendritic cell differentiation [Hoxb8-FL ATAC-Seq]

Project description:The development of all dendritic cells (DCs) including antigen-presenting conventional DCs (cDCs) and cytokine-producing plasmacytoid DCs (pDCs) is controlled by the growth factor Flt3 ligand (Flt3L) and its receptor Flt3. We genetically dissected this common Flt3L-driven pathway of DCs differentiation using CRISPR/Cas9-based dropout screening in a Flt3L-dependent progenitor cell line. Genome-wide screening identified multiple regulators of DC differentiation including the glycosylphosphatidylinositol transamidase complex and arginine methyltransferase Carm1, whose role was confirmed in vivo. It also showed that negative regulators of mTOR signaling, including the subunits of TSC and GATOR1 complexes, restricted progenitor growth but enabled DC differentiation, demonstrating that a TSC- and GATOR1-mediated shutdown of mTOR is required for the process. An orthogonal screen focused on transcriptional regulators showed that Trim33 (TIF-1g) is required for DC differentiation. Conditional targeting in vivo revealed an essential role of Trim33 in the development of all DCs, but not of monocytes or granulocytes. In particular, inducible deletion of Trim33 caused a rapid loss of all DC progenitors, pDCs and the cross-presenting cDC1 subset. The loss of Trim33 from DC progenitors caused spontaneous interferon and inflammatory response, aberrant induction of macrophage-specific genes, and failure to induce DC differentiation program. Collectively, these data elucidate common mechanisms that control Flt3L-driven differentiation of the entire DC lineage, and identify Trim33 as its essential regulator.

2024-04-12 | GSE202582 | GEO

Leukemia-associated activating mutation of Flt3 expands dendritic cells and alters T cell responses

Project description:One of the most common genetic alterations in acute myeloid leukemia is the internal tandem duplication (ITD) in the FLT3 receptor for cytokine FLT3 ligand (FLT3L). The constitutively active FLT3-ITD promotes the expansion of transformed progenitors, but also has pleiotropic effects on normal hematopoiesis. We analyzed the effect of FLT3-ITD on dendritic cells (DCs), which express FLT3 and can be expanded by FLT3L administration. We report that young pre-leukemic mice with the Flt3ITD knock-in allele manifest an expansion of all DCs including classical (cDCs) and plasmacytoid (pDCs). The expansion originated in DC progenitors, occurred in a cell-intrinsic manner and was further enhanced in Flt3ITD/ITD mice. The mutation caused the downregulation of Flt3 on the surface of DCs and reduced their responsiveness to Flt3L. Flt3ITD mice showed enhanced capacity to support T cell proliferation, including a cell-extrinsic expansion of regulatory T cells (Tregs). Accordingly, these mice restricted alloreactive T cell responses during graft-versus-host reaction, but failed to control autoimmunity in the absence of Tregs. Thus, the FLT3-ITD mutation directly affects DC development, thereby indirectly modulating T cell homeostasis and supporting Treg expansion. This effect of FLT3-ITD may subvert immunosurveillance and promote leukemogenesis in a cell-extrinsic manner.

2016-01-28 | GSE76132 | GEO

Bcl11a controls Flt3 expression in early hematopoietic progenitors and is required for pDC development in vivo

Project description:Bcl11a is a transcription factor known to regulate lymphoid and erythroid development. Recent bioinformatic analysis of global gene expression patterns has suggested a role for Bcl11a in the development of dendritic cell (DC) lineages. We tested this hypothesis by analyzing the development of DC and other lineages in Bcl11a(-/-) mice. We show that Bcl11a is required for expression of IL-7 receptor (IL-7R) and Flt3 in early hematopoietic progenitor cells. The loss of IL-7R(+) common lymphoid progenitors accounts for previously described lymphoid defects in Bcl11a(-/-) mice. In addition, we found severely decreased numbers of plasmacytoid dendritic cells (pDCs) in Bcl11a(-/-) fetal livers and in the bone marrow of Bcl11a(-/-) fetal liver chimeras. Moreover, Bcl11a(-/-) cells show severely impaired in vitro development of Flt3L-derived pDCs and classical DCs (cDCs). In contrast, we found normal in vitro development of DCs from Bcl11a(-/-) fetal liver cells treated with GM-CSF. These results suggest that the persistent cDC development observed in Bcl11a(-/-) fetal liver chimeras reflects derivation from a Bcl11a- and Flt3-independent pathway in vivo. We compared global gene expression by microarray for donor-derived wild-type and Bcl11a(-/-) populations isolated from chimeric bone marrow to identify Bcl11a target genes that explain its role in hematopoietic progenitors. GMP and MPP populations were sorted from fetal liver chimeras and pooled by donor genotype. RNA was isolated using an RNAqueous-Micro Kit (Ambion) and submitted for amplification, labeling and hybridization. Expression values were analyzed after RMA quantile normalization using ArrayStar software (DNASTAR).

2013-05-06 | E-GEOD-46270 | biostudies-arrayexpress

Bcl11a controls Flt3 expression in early hematopoietic progenitors and is required for pDC development in vivo

2013-05-06 | GSE46270 | GEO

Dendritic cell lineage commitment is instructed by distinct cytokine signals

Project description:Dendritic cells (DC) develop from hematopoietic stem cells, which is guided by instructive signals through cytokines. DC development progresses from multipotent progenitors (MPP) via common DC progenitors (CDP) into DC. Flt3 ligand (Flt3L) signaling via the Flt3/Stat3 pathway is of pivotal importance for DC development under steady state conditions. Additional factors produced during steady state or inflammation, such as TGF-beta1 or GM-CSF, also influence the differentiation potential of MPP and CDP. Here, we studied how gp130, GM-CSF and TGF-beta1 signaling influence DC lineage commitment from MPP to CDP and further into DC. We observed that activation of gp130 signaling promotes expansion of MPP. Additionally, gp130 signaling inhibited Flt3L-driven DC differentiation, but had little effect on GM-CSF-driven DC development. The inflammatory cytokine GM-CSF induces differentiation of MPP into inflammatory DC and blocks steady state DC development. Global transcriptome analysis revealed a GM-CSF-driven gene expression repertoire that primes MPP for differentiation into inflammatory DC. Finally, TGF-beta1 induces expression of DC-lineage affiliated genes in MPP, including Flt3, Irf-4 and Irf-8. Under inflammatory conditions, however, the effect of TGF- beta1 is altered: Flt3 is not upregulated, indicating that an inflammatory environment inhibits steady state DC development. Altogether, our data indicate that distinct cytokine signals produced during steady state or inflammation have a different outcome on DC lineage commitment and differentiation. 6 samples in total. Multipotent progenitor - GM-MPP_1 - GM-MPP_2 Dendritic cell - GM-DC_1 - GM-DC_2 Dendritic cell plus TNFa - GM-TNFa-DC_1 - GM-TNFa-DC_2

2011-11-13 | E-GEOD-29241 | biostudies-arrayexpress

Dendritic cell lineage commitment is instructed by distinct cytokine signals

2011-11-13 | GSE29241 | GEO

TGF-β1 Accelerates Dendritic Cell Differentiation from Common Dendritic Cell Progenitors (CDPs) and Directs Subset Specification Towards Conventional Dendritic Cells

Project description:Dendritic cells (DCs) in lymphoid tissue comprise conventional DCs (cDCs) and plasmacytoid DCs (pDCs) that develop from common DC progenitors (CDPs). CDPs are Flt3+c-kitintM-CSFR+ and reside in bone marrow. Here we describe a two-step culture system that recapitulates DC development from c-kithiFlt3-/lo multipotent progenitors (MPPs) into CDPs and further into cDC and pDC subsets. MPPs and CDPs are amplified in vitro with Flt3 ligand, stem cell factor, hyper-IL-6 and insulin- like growth factor-1. The four-factor cocktail readily induces self-renewal of MPPs and their progression into CDPs and has no self-renewal activity on CDPs. The amplified CDPs respond to all known DC poietins and generate all lymphoid tissue DCs in vivo and in vitro. Additionally, in vitro CDPs recapitulate the cell surface marker and gene expression profile of in vivo CDPs and possess a DC-primed transcription profile. Transforming growth factor-β1 (TGF-β1) impacts on CDPs and directs their differentiation towards cDCs. Genome-wide gene expression profiling of TGF-β1-induced genes identified transcription factors, such as interferon regulatory factor-4 (IRF-4) and RelB, that are implicated as instructive factors for cDC subset specification. TGF-β1 also induced the transcription factor inhibitor of differentiation/DNA binding 2 (Id2) that suppresses pDC development. Thus, TGF-β1 directs CDP differentiation into cDC by inducing both cDC instructive factors and pDC inhibitory factors.

2010-10-04 | GSE22432 | GEO

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