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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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A negative feedback loop of transcription factors specifies alternative dendritic cell chromatin states (ChIP-Seq)

ABSTRACT: During hematopoiesis, cells originating from the same stem cell reservoir differentiate into distinct cell types. The mechanisms enabling common progenitors to differentiate into distinct cell fates are not fully understood. Here, we identify chromatin-regulating and cell-fate-determining transcription factors (TF) governing dendritic cell (DC) development by annotating the enhancer and promoter landscapes of the DC lineage. Combining these analyses with detailed over-expression, knockdown and ChIP-Seq studies, we show that Irf8 functions as a plasmacytoid DC epigenetic and fate-determining TF, regulating massive, cell-specific chromatin changes in thousands of pDC enhancers. Importantly, Irf8 forms a negative feedback loop with Cebpb, a monocyte-derived DC epigenetic fate-determining TF. We show that using this circuit logic, differential activity of TF can stably define epigenetic and transcriptional states, regardless of the microenvironment. More broadly, our study proposes a general paradigm that allows closely related cells with a similar set of signal-dependent factors to generate differential and persistent enhancer landscapes. Here analyzed 2 experiments, each one contains samples of moDC and pDC ex vivo cultured cells. The first experiment contains 32 samples of moDC and pDC following stimulation with various TLR stimulators. The second experiment contains 8 samples of moDC and pDC following perturbations; Cebpb and Irf8 knock down or over expression.

ORGANISM(S): Mus musculus

SUBMITTER: Ido Amit

PROVIDER: E-GEOD-62702 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A negative feedback loop of transcription factors specifies alternative dendritic cell chromatin states (RNA-Seq)

Project description:During hematopoiesis, cells originating from the same stem cell reservoir differentiate into distinct cell types. The mechanisms enabling common progenitors to differentiate into distinct cell fates are not fully understood. Here, we identify chromatin-regulating and cell-fate-determining transcription factors (TF) governing dendritic cell (DC) development by annotating the enhancer and promoter landscapes of the DC lineage. Combining these analyses with detailed over-expression, knockdown and ChIP-Seq studies, we show that Irf8 functions as a plasmacytoid DC epigenetic and fate-determining TF, regulating massive, cell-specific chromatin changes in thousands of pDC enhancers. Importantly, Irf8 forms a negative feedback loop with Cebpb, a monocyte-derived DC epigenetic fate-determining TF. We show that using this circuit logic, differential activity of TF can stably define epigenetic and transcriptional states, regardless of the microenvironment. More broadly, our study proposes a general paradigm that allows closely related cells with a similar set of signal-dependent factors to generate differential and persistent enhancer landscapes. Here analyzed 2 experiments, each one contains samples of moDC and pDC ex vivo cultured cells. The first experiment contains 32 samples of moDC and pDC following stimulation with various TLR stimulators. The second experiment contains 8 samples of moDC and pDC following perturbations; Cebpb and Irf8 knock down or over expression.

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A negative feedback loop of transcription factors specifies alternative dendritic cell chromatin states (ATAC-Seq)

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2014-12-14 | E-GEOD-62703 | biostudies-arrayexpress

A negative feedback loop of transcription factors specifies alternative dendritic cell chromatin states (RNA-Seq)

2014-12-14 | GSE62704 | GEO

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L-Myc expression by dendritic cells is required for optimal T-cell priming

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L-Myc expression by dendritic cells is required for optimal T-cell priming

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Optimization of the Irf8 +32 kb enhancer disrupts dendritic cell lineage segregation

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Project description:Dendritic cells (DC) are professional antigen presenting cells that develop from hematopoietic stem cells through successive steps of lineage commitment and differentiation. Multipotent progenitors (MPP) are committed to DC restricted common DC progenitors (CDP), which differentiate into specific DC subsets, classical DC (cDC) and plasmacytoid DC (pDC). To determine epigenetic states and regulatory circuitries during DC differentiation, we measured consecutive changes of genome-wide gene expression, histone modification and transcription factor occupancy during the sequel MPP-CDP-cDC/pDC. Specific histone marks in CDP reveal a DC-primed epigenetic signature, which is maintained and reinforced during DC differentiation. Epigenetic marks and transcription factor PU.1 occupancy increasingly coincide upon DC differentiation. By integrating PU.1 occupancy and gene expression we devised a transcription factor regulatory circuitry for DC commitment and subset specification. The circuitry provides the transcription factor hierarchy that drives the sequel MPP-CDP-cDC/pDC, including Irf4, Irf8, Tcf4, Spib and Stat factors. The circuitry also includes feedback loops inferred for individual or multiple factors, which stabilize distinct stages of DC development and DC subsets. In summary, here we describe the basic regulatory circuitry of transcription factors that drives DC development.

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