Hi-C sequencing data of WT and Zeb2 enhancer mutant splenic CD8+ T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA718327 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14097436_1.fastq.gz | Fastqsanger.gz | |||
| SRR14097436_2.fastq.gz | Fastqsanger.gz | |||
| SRR14097437_1.fastq.gz | Fastqsanger.gz | |||
| SRR14097437_2.fastq.gz | Fastqsanger.gz |
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Project description:To evaluate the impact of -165-kb Zeb2 enhancer deletion on 3D chromatin structure, we performed in situ Hi-C analysis of WT and Zeb2 –165–/– splenic CD8+ T cells, which showed no significant global changes on the structure of chromosome 2
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Project description:T-bet is critical for cytotoxic T lymphocyte (CTL) differentiation, but it is unclear how it operates in a graded manner in the formation of both terminal effector and memory precursor cells during infection. We find that at high concentrations T-bet induced expression of Zeb2 mRNA, which then triggered CTLs to adopt terminally differentiated states. ZEB2 and T-bet cooperate to switch on a terminal CTL differentiation program, while simultaneously repressing genes necessary for central memory CTL development. Chromatin immunoprecipitation sequencing (ChIP-seq) showed that a large proportion of these genes were bound by T-bet, and this binding was altered by ZEB2 deficiency. Furthermore, T-bet overexpression could not fully bypass ZEB2 function. Thus, the coordinated actions of T-bet and ZEB2 outline a novel genetic pathway that forces commitment of CTLs to terminal differentiation, thereby restricting their memory cell potential. Splenocyte derived CD8+ T cells from C57BL/6 mice with either a wildtype (WT) (GzmB-Cre Zeb2+/+) or GzmB-Cre Zeb2-fl/fl (Zeb2-/-) backgrounds, following 8 days post infection with LCMV-Armstrong, were subsetted into KLRG1-hi/IL-7R-lo populations (terminal effectors, TE) or KLRG1-lo/IL-7R-hi (memory precursors, MP) populations. Four experimental groups, each with 3 samples, comprised of TE+WT, MP+WT, TE+ZEB2-/-, and MP+ZEB2-/-, were profiled for gene expression utilizing a polyA RNA prep and hybridized to the Illumina microarray platform IlluminaWG-v2.0.
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Project description:The transcriptional repressor Zeb2 regulates development of many cell fates among somatic, neural and hematopoietic lineages, but the basis for its requirement in these diverse linages is unclear. Our recent study uncovered a mutually repressive regulatory circuit between Id2 and Zeb2, and predicted that Zeb2 should be positively regulated by members of the E protein family of transcription factors. Here, we identified a 400bp enhancer region located 165 kilobases (kb) upstream of the Zeb2 transcriptional start site (TSS) that binds the E proteins E2A and E2-2 at several E-box motifs and is active in hematopoietic lineages. Germline deletion of this 400bp region (Zeb2 –165–/– mice) specifically prevented Zeb2 expression in hematopoietic stem cell (HSC) derived lineages. Zeb2 –165–/– mice lacked development of pDCs, monocytes, and B cells. Surprisingly, all macrophages in Zeb2 –165–/– mice were exclusively of embryonic origin. Using single-cell chromatin profiling, we identified a second Zeb2 enhancer located at +164kb that is selectively active in embryonically derived lineages, but not in lineages derived from HSCs. Thus, Zeb2 expression in adult, but not embryonic, hematopoiesis is selectively controlled by the –165kb Zeb2 enhancer.
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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.
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