Cis-regulation between Irf8 enhancers during cDC1 development (CUT&RUN)
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ABSTRACT:
PROVIDER: PRJNA906526 | ENA |
REPOSITORIES: ENA
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Project description:Type 1 classical dendritic cells (cDC1s) development requires the transcription factor IRF8, and IRF8 mutations cause severe combined immunodeficiency, including disseminated bacille Calmette-Guérin (BCG) disease. IRF8 regulated enhancers are required for Irf8 expression in early DC progenitors and mature cDC1s. The E-protein-dependent +41 kb enhancer gains accessibility and activates transcription in common DC progenitors (CDPs), and its depletion abrogated pre-cDC1s specification. The Batf3-dependent +32 kb enhancer gains accessibility and activates transcription in pre-cDC1 progenitors, and its depletion impaired cDC1 maturation. The +32 kb Irf8 enhancer locus bears an enhancer transcript, and the production of enhancer RNA (eRNA) Gm39266 is dependent on +41 kb Irf8 enhancer. It was unclear whether the +32 kb and +41 kb enhancers act independently or cooperate to regulate Irf8 expression. We dissected the mechanisms using +32/+41 compound heterozygous mice, and found that while the +41 kb enhancer suffices for pre-cDC1 progenitor specification, the +32 kb and +41 kb enhancers must reside on one allele to support cDC1 maturation. The +41 kb enhancer cis-regulates chromatin accessibility and BATF3 binding at +32 kb enhancer, independent of eRNA Gm39266 transcripts or transcription across +32 kb Irf8 enhancer.
2023-03-15 | GSE218991 | GEO
Project description:Type 1 classical dendritic cells (cDC1s) development requires the transcription factor IRF8, and IRF8 mutations cause severe combined immunodeficiency, including disseminated bacille Calmette-Guérin (BCG) disease. IRF8 regulated enhancers are required for Irf8 expression in early DC progenitors and mature cDC1s. The E-protein-dependent +41 kb enhancer gains accessibility and activates transcription in common DC progenitors (CDPs), and its depletion abrogated pre-cDC1s specification. The Batf3-dependent +32 kb enhancer gains accessibility and activates transcription in pre-cDC1 progenitors, and its depletion impaired cDC1 maturation. The +32 kb Irf8 enhancer locus bears an enhancer transcript, and the production of enhancer RNA (eRNA) Gm39266 is dependent on +41 kb Irf8 enhancer. It was unclear whether the +32 kb and +41 kb enhancers act independently or cooperate to regulate Irf8 expression. We dissected the mechanisms using +32/+41 compound heterozygous mice, and found that while the +41 kb enhancer suffices for pre-cDC1 progenitor specification, the +32 kb and +41 kb enhancers must reside on one allele to support cDC1 maturation. The +41 kb enhancer cis-regulates chromatin accessibility and BATF3 binding at +32 kb enhancer, independent of eRNA Gm39266 transcripts or transcription across +32 kb Irf8 enhancer.
2023-03-15 | GSE218990 | GEO
Project description:Cis-regulation between Irf8 enhancers during cDC1 development
| PRJNA906523 | ENA
Project description:Cis-regulation between Irf8 enhancers during cDC1 development (ATAC-Seq)
| PRJNA906525 | ENA
Project description:Conventional dendritic cells (cDC) consist of two functionally and phenotypically distinct subsets, cDC1 and cDC2, whose development is dependent on distinct sets of transcription factors. Interferon regulatory factor 8 (IRF8) is required at multiple stages of cDC1 development, but its role in mature cDC1 remains unclear. Here we used XCR1-cre to delete Irf8 in committed cDC1 and demonstrate that Irf8 is required for maintaining the identify of cDC1 but not their survival. In the absence of Irf8, committed cDC1 (“ex-cDC1”) acquired the transcriptional, functional and chromatin accessibility properties of cDC2. This conversion was independent on Irf4 and was associated with decreased accessibility in putative IRF8, Batf3 and composite AP-1-IRF (AICE) binding elements, together with increased accessibility of cDC2 associated transcription factor binding elements. Thus, IRF8 expression by committed cDC1 is required for preventing their conversion into cDC2.
2022-06-21 | GSE168477 | GEO
Project description:Classical type 1 dendritic cells (cDC1s) are required for anti-viral and anti-tumor immunity, which has motivated a need to understand their development. The development of the cDC1 progentitor requires an E protein–dependent enhancer located 41 kilobases downstream of the transcription start site of the transcription factor IRF8 (+41 kb Irf8 enhancer) but its maturation instead requires the BATF3-dependent +32 kb Irf8 enhancer. To understand this switch, we performed single-cell RNA sequencing of the common dendritic cell progenitor (CDP) and identified a cluster of cells that expressed transcription factors that influence cDC1 development, such as Nfil3, Id2, and Zeb2. Genetic epistasis among these factors revealed that Nfil3 expression is required for the transition from Zeb2hi and Id2lo CDPs to Zeb2lo and Id2hi CDPs, which represent the earliest committed cDC1 progenitors. This genetic circuit blocks E protein activity to exclude plasmacytoid DC potential and explains the switch in Irf8 enhancer usage during cDC1 development.
2019-06-23 | GSE132770 | GEO
Project description:We used gene expression microarrays to determine if Batf3 and the IRF8 +32 kb enhancer are required to sustain IRF8 expression in the pre-cDC1.
2019-06-23 | GSE132768 | GEO
Project description:To understand the mechanism underlying monocyte and dendritic cell development through the regulation of Irf8 expression by the 56 kb downstream (+56 kb) Irf8 enhancer, we performed epigenetic profiling of bone marrow cells and splenocytes from wild-type, the Irf8 +56 kb enhancer-deficient, and IRF8-deficient mice. Taken together with the transcriptome analysis of mononuclear phagocyte lineage cells in these mice, the Irf8 +56 kb enhancer-mediated high Irf8 expression in hematopoietic progenitor cells promote type 1 classical dendritic cell (cDC1) differentiation, while low Irf8 expression in progenitors led to Ly6C+ monocyte development. In addition, IRF8 ChIP-seq of mature cDC1s and monocytes suggested that IRF8 regulates enhancers in cooperation with different transcription factors in each lineage in its expression level.
2020-12-20 | GSE149757 | GEO
Project description:Autoactivation of lineage-determining transcription factors (TFs) mediates bistable expression to generate distinct cell phenotypes essential for complex body plans. Classical dendritic cells type 1 (cDC1) and type 2 (cDC2) provide non-redundant functions required for defense against distinct immune challenges. Interferon Regulatory Factor 8 (IRF8), the cDC1 lineage-determining TF, undergoes autoactivation in cDC1 progenitors to establish cDC1 identity, yet its expression is downregulated during cDC2 differentiation by an unknown mechanism. This study reveals that the Irf8 +32 kb enhancer, responsible for IRF8 autoactivation, has been tuned to possess low-affinity IRF8 binding sites. Incorporation of multiple high-affinity IRF8 binding sites into the Irf8 +32 kb enhancer induces erroneous IRF8 autoactivation in specified cDC2 progenitors, causing their redirection towards cDC1 and a novel hybrid DC subset with mixed lineage phenotypes. These developmental alterations critically impair both cDC1- and cDC2-dependent arms of immunity. Collectively, our findings underscore the significance of enhancer suboptimization in the developmental segregation of classical dendritic cells required for normal immune function.
2024-08-18 | GSE270060 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-03-14 | GSE218992 | GEO