Ablation of cDC2 development by triple mutations within the Zeb2 enhancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA779440 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14472212.fastq.gz | Fastqsanger.gz | |||
| SRR14472213.fastq.gz | Fastqsanger.gz | |||
| SRR16892200_1.fastq.gz | Fastqsanger.gz | |||
| SRR16892200_2.fastq.gz | Fastqsanger.gz | |||
| SRR16892201_1.fastq.gz | Fastqsanger.gz |
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Project description:The divergence of the common dendritic cell progenitor (CDP) into the conventional type 1 and type 2 dendritic cell (cDC1 and cDC2, respectively) lineages is poorly understood. Some transcription factors act in the commitment of already specified progenitors-such as BATF3, which stabilizes Irf8 autoactivation at the +32 kb Irf8 enhancer-but the mechanisms controlling the initial divergence of CDPs remain unknown. Here we report the transcriptional basis of CDP divergence and describe the first requirements for pre-cDC2 specification. Genetic epistasis analysis suggested that Nfil3 acts upstream of Id2, Batf3 and Zeb2 in cDC1 development but did not reveal its mechanism or targets. Analysis of newly generated NFIL3 reporter mice showed extremely transient NFIL3 expression during cDC1 specification. CUT&RUN and chromatin immunoprecipitation followed by sequencing identified endogenous NFIL3 binding in the -165 kb Zeb2 enhancer at three sites that also bind the CCAAT-enhancer-binding proteins C/EBPα and C/EBPβ. In vivo mutational analysis using CRISPR-Cas9 targeting showed that these NFIL3-C/EBP sites are functionally redundant, with C/EBPs supporting and NFIL3 repressing Zeb2 expression at these sites. A triple mutation of all three NFIL3-C/EBP sites ablated Zeb2 expression in myeloid, but not lymphoid progenitors, causing the complete loss of pre-cDC2 specification and mature cDC2 development in vivo. These mice did not generate T helper 2 (TH2) cell responses against Heligmosomoides polygyrus infection, consistent with cDC2 supporting TH2 responses to helminths. Thus, CDP divergence into cDC1 or cDC2 is controlled by competition between NFIL3 and C/EBPs at the -165 kb Zeb2 enhancer.
2022-04-19 | GSE188579 | GEO
Project description:The divergence of the common dendritic cell progenitor (CDP) into specified progenitors for the cDC1 and cDC2 dendritic cells subsets is poorly understood. Some transcription factors (TFs) act in commitment of already specified progenitors, such as Batf3 which stabilizes Irf8 autoactivation at the +32 kb Irf8 enhancer, but the mechanism of CDP divergence remains unknown. Here, we report the transcriptional basis of CDP divergence and describe the first requirements for pre-cDC2 specification. Genetic epistasis analysis suggested that Nfil3 acts upstream of Id2, Batf3, and Zeb2 in cDC1 development but has not revealed its mechanism or targets. Analysis of newly generated NFIL3 reporter mice showed extremely transient NFIL3 expression during cDC1 specification. CUT&RUN and ChIP-seq analysis identified endogenous NFIL3 binding in the –165 kb Zeb2 enhancer at three sites that also bind CCAAT-enhancer-binding proteins C/EBPa and C/EBPb. In vivo mutational analysis using CRISPR/Cas9 targeting showed that these NFIL3/C/EBP sites are functionally redundant, with C/EBPs supporting and NFIL3 repressing Zeb2 expression at these sites, respectively. Mutation of all three NFIL3/C/EBP sites ablated Zeb2 expression in myeloid, but not lymphoid progenitors, causing complete loss of pre-cDC2 specification and mature cDC2 development in vivo. These mice failed to generate TH2 responses against H. polygyrus infection, consistent with cDC2 supporting TH2 responses to helminths. Thus, CDP divergence is controlled by competition between NFIL3 and C/EBPs at the –165 kb Zeb2 enhancer.
2022-04-19 | GSE174108 | GEO
Project description:The divergence of the common dendritic cell progenitor (CDP) into specified progenitors for the cDC1 and cDC2 dendritic cells subsets is poorly understood. Some transcription factors (TFs) act in commitment of already specified progenitors, such as Batf3 which stabilizes Irf8 autoactivation at the +32 kb Irf8 enhancer, but the mechanism of CDP divergence remains unknown. Here, we report the transcriptional basis of CDP divergence and describe the first requirements for pre-cDC2 specification. Genetic epistasis analysis suggested that Nfil3 acts upstream of Id2, Batf3, and Zeb2 in cDC1 development but has not revealed its mechanism or targets. Analysis of newly generated NFIL3 reporter mice showed extremely transient NFIL3 expression during cDC1 specification. CUT&RUN and ChIP-seq analysis identified endogenous NFIL3 binding in the –165 kb Zeb2 enhancer at three sites that also bind CCAAT-enhancer-binding proteins C/EBPa and C/EBPb. In vivo mutational analysis using CRISPR/Cas9 targeting showed that these NFIL3/C/EBP sites are functionally redundant, with C/EBPs supporting and NFIL3 repressing Zeb2 expression at these sites, respectively. Mutation of all three NFIL3/C/EBP sites ablated Zeb2 expression in myeloid, but not lymphoid progenitors, causing complete loss of pre-cDC2 specification and mature cDC2 development in vivo. These mice failed to generate TH2 responses against H. polygyrus infection, consistent with cDC2 supporting TH2 responses to helminths. Thus, CDP divergence is controlled by competition between NFIL3 and C/EBPs at the –165 kb Zeb2 enhancer.
2022-04-19 | GSE188564 | GEO
Project description:The divergence of the common dendritic cell progenitor (CDP) into specified progenitors for the cDC1 and cDC2 dendritic cells subsets is poorly understood. Some transcription factors (TFs) act in commitment of already specified progenitors, such as Batf3 which stabilizes Irf8 autoactivation at the +32 kb Irf8 enhancer, but the mechanism of CDP divergence remains unknown. Here, we report the transcriptional basis of CDP divergence and describe the first requirements for pre-cDC2 specification. Genetic epistasis analysis suggested that Nfil3 acts upstream of Id2, Batf3, and Zeb2 in cDC1 development but has not revealed its mechanism or targets. Analysis of newly generated NFIL3 reporter mice showed extremely transient NFIL3 expression during cDC1 specification. CUT&RUN and ChIP-seq analysis identified endogenous NFIL3 binding in the –165 kb Zeb2 enhancer at three sites that also bind CCAAT-enhancer-binding proteins C/EBPa and C/EBPb. In vivo mutational analysis using CRISPR/Cas9 targeting showed that these NFIL3/C/EBP sites are functionally redundant, with C/EBPs supporting and NFIL3 repressing Zeb2 expression at these sites, respectively. Mutation of all three NFIL3/C/EBP sites ablated Zeb2 expression in myeloid, but not lymphoid progenitors, causing complete loss of pre-cDC2 specification and mature cDC2 development in vivo. These mice failed to generate TH2 responses against H. polygyrus infection, consistent with cDC2 supporting TH2 responses to helminths. Thus, CDP divergence is controlled by competition between NFIL3 and C/EBPs at the –165 kb Zeb2 enhancer.
2022-04-19 | GSE188482 | GEO
Project description:Ablation of cDC2 specification by triple mutations in the Zeb2 enhancer [CUT&RUN]
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Project description:Ablation of cDC2 specification by triple mutations in the Zeb2 enhancer [ChIP-Seq]
| PRJNA728352 | ENA
Project description:Ablation of cDC2 specification by triple mutations in the Zeb2 enhancer [RNA-seq]
| PRJNA779428 | ENA
Project description:The divergence of the common dendritic cell progenitor1-3 (CDP) into the conventional type 1 and type 2 dendritic cell (cDC1 and cDC2, respectively) lineages4,5 is poorly understood. Some transcription factors act in the commitment of already specified progenitors-such as BATF3, which stabilizes Irf8 autoactivation at the +32 kb Irf8 enhancer4,6-but the mechanisms controlling the initial divergence of CDPs remain unknown. Here we report the transcriptional basis of CDP divergence and describe the first requirements for pre-cDC2 specification. Genetic epistasis analysis7 suggested that Nfil3 acts upstream of Id2, Batf3 and Zeb2 in cDC1 development but did not reveal its mechanism or targets. Analysis of newly generated NFIL3 reporter mice showed extremely transient NFIL3 expression during cDC1 specification. CUT&RUN and chromatin immunoprecipitation followed by sequencing identified endogenous NFIL3 binding in the -165 kb Zeb2 enhancer8 at three sites that also bind the CCAAT-enhancer-binding proteins C/EBPα and C/EBPβ. In vivo mutational analysis using CRISPR-Cas9 targeting showed that these NFIL3-C/EBP sites are functionally redundant, with C/EBPs supporting and NFIL3 repressing Zeb2 expression at these sites. A triple mutation of all three NFIL3-C/EBP sites ablated Zeb2 expression in myeloid, but not lymphoid progenitors, causing the complete loss of pre-cDC2 specification and mature cDC2 development in vivo. These mice did not generate T helper 2 (TH2) cell responses against Heligmosomoides polygyrus infection, consistent with cDC2 supporting TH2 responses to helminths9-11. Thus, CDP divergence into cDC1 or cDC2 is controlled by competition between NFIL3 and C/EBPs at the -165 kb Zeb2 enhancer.
| S-EPMC10358283 | biostudies-literature
Project description:Plasmacytoid dendritic cells (pDCs) develop from pre-pDCs, while two lineages of conventional DCs (cDC1s and cDC2s) develop from lineage-committed pre-cDCs. A number of transcription factors (TFs) have been implicated in regulating the development of pDCs (E2-2, Id2) and cDC1s (IRF8, Id2 and Batf3) however, those required for the early commitment of pre-cDCs towards the cDC2 lineage are unknown. Here we identified the TF Zinc finger E box binding homeobox 2 (Zeb2), to play a crucial role in regulating DC development. Zeb2 was expressed from the pre-pDC and pre-cDC stage onwards, and highly expressed in mature pDCs and cDC2s. Mice conditionally lacking Zeb2 in CD11c+ cells had a cell intrinsic reduction in pDCs and cDC2s, coupled with an increase in cDC1s. Conversely, mice in which CD11c+ cells overexpressed Zeb2 displayed a reduction in cDC1s. This was accompanied by altered expression of Id2, which was upregulated in cDC2s and pDCs from conditional knock-out mice. Zeb2 ChIP analysis revealed Id2 to be a direct target of Zeb2. Thus, we conclude that Zeb2 regulates commitment to both the cDC2 and pDC lineages through repression of Id2.
2016-05-01 | GSE79903 | GEO
Project description:infarct size and subsequent deterioration in function. The identification of factors that enhance cardiac repair by the restoration of the vascular network is, therefore, of great significance. Here, we show that the transcription factor Zinc finger E-box-binding homeobox 2 (ZEB2) is increased in stressed cardiomyocytes and induces a cardioprotective cross-talk between cardiomyocytes and endothelial cells to enhance angiogenesis after ischemia. Single-cell sequencing indicates ZEB2 to be enriched in injured cardiomyocytes. Cardiomyocyte-specific deletion of ZEB2 results in impaired cardiac contractility and infarct healing post-myocardial infarction (post-MI), while cardiomyocyte-specific ZEB2 overexpression improves cardiomyocyte survival and cardiac function. We identified Thymosin 4 (TMSB4) and Prothymosin (PTMA) as main paracrine factors released from cardiomyocytes to stimulate angiogenesis by enhancing endothelial cell migration, and whose regulation is validated in our in vivo models. Therapeutic delivery of ZEB2 to cardiomyocytes in the infarcted heart induces the expression of TMSB4 and PTMA, which enhances angiogenesis and prevents cardiac dysfunction. These findings reveal ZEB2 as a beneficial factor during ischemic injury, which may hold promise for the identification of new therapies.
2021-03-23 | PXD022212 | Pride