Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA385830 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5516290.fastq.gz | Fastqsanger.gz | |||
| SRR5516291.fastq.gz | Fastqsanger.gz | |||
| SRR5516282.fastq.gz | Fastqsanger.gz | |||
| SRR5516292.fastq.gz | Fastqsanger.gz | |||
| SRR5516283.fastq.gz | Fastqsanger.gz |
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Project description:<p>Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. Mutations in the p63 DNA-binding domain are associated with Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate (EEC) syndrome. Underlying molecular mechanism of these mutations however remain unclear. Here we characterized the transcriptome and epigenome of p63 mutant keratinocytes derived from EEC patients. The transcriptome of p63 mutant keratinocytes deviated from the normal epidermal cell identity. Epigenomic analyses showed an altered enhancer landscape in p63 mutant keratinocytes contributed by loss of p63-bound active enhancers and by unexpected gain of enhancers. The gained enhancers were frequently bound by deregulated transcription factors such as RUNX1. Reversing RUNX1 overexpression partially rescued deregulated gene expression and the altered enhancer landscape. Our findings identify an unreported disease mechanism whereby mutant p63 rewires the enhancer landscape and affects epidermal cell identity, consolidating the pivotal role of p63 in controlling the enhancer landscape of epidermal keratinocytes.</p>
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Project description:Transcription factor (TF) reporter mice have proved integral to the characterization of murine innate lymphoid cell (ILC) development and function. Here, we implemented a CRISPR/Cas9-generated combinatorial reporter approach for the simultaneous resolution of several key TFs throughout ILC development in both the fetal liver and adult bone marrow. We demonstrate that the Tcf7-expressing early innate lymphoid progenitor (EILP) and the common helper innate lymphoid progenitor (CHILP) both contain a heterogeneous mixture of committed ILC and Lymphoid Tissue-inducer (LTi) precursors, rather than a shared precursor to these lineages. Moreover, the earliest specified precursor to the LTi lineage was identified upstream of these populations, prior to the expression of Tcf7. These findings match dynamic changes in chromatin accessibility associated with the expression of key TFs (ie. Gata3 and Rorc), highlighting the distinct origins of ILC and LTi lineages at the epigenetic and functional levels, and provide a revised map for ILC development.
2020-09-28 | GSE150763 | GEO
Project description:Innate lymphoid cells (ILCs) are recently identified lymphocytes that limit infection and promote tissue repair at mucosal surfaces. However, the pathways underlying ILC development remain unclear. Here we show that the transcription factor NFIL3 directs the development of a committed bone marrow precursor that differentiates into all known ILC lineages. NFIL3 was required in the common lymphoid progenitor (CLP), and was essential for the differentiation of CLP, a bone marrow cell population that gives rise to all known ILC lineages. Clonal differentiation studies revealed that CXCR6+ cells within the CLP population differentiate into all ILC lineages but not T- and B-cells. We further show that NFIL3 governs ILC development by directly regulating expression of the transcription factor TOX. These findings establish that NFIL3 directs the differentiation of a committed ILC precursor that gives rise to all ILC lineages and provide insight into the defining role of NFIL3 in ILC development. This experiment is to compare gene expression profiles between wild-type and Nfil3-/- common lymphoid progenitor (CLP) cells to identify genes regulated by NFIL3. There are 6 samples in this experiment, including 3 biological replicates for wild-type CLPs and 3 biological replicates for Nfil3-/- CLPs. All mice used are on the C57BL/6 background.
2014-10-16 | E-GEOD-62337 | biostudies-arrayexpress
Project description:PHF6 mutations (PHF6MT) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of PHF6 in MN. Our comprehensive genomic analyses focused on three main findings. Firstly, we revealed a different pattern of genes correlating with PHF6MT in male and female cases. When analyzing male and female cases separately, in only male cases, RUNX1 and U2AF1 were co-mutated with PHF6. In contrast, female cases revealed co-occurrence of ASXL1 mutations and X-chromosome deletions with PHF6MT. Next, proteomics analysis revealed a direct interaction between PHF6 and the pioneer transcription factor RUNX1. Both proteins co-localize in active enhancer regions that define the context of lineage differentiation. Finally, we demonstrated a negative prognostic role of PHF6MT, especially in association with RUNX1. The negative effects on survival were additive as PHF6MT cases with RUNX1 mutations had worse outcomes when compared to cases carrying single mutation or wild-type.
2023-11-21 | PXD042441 | Pride
Project description:The hematopoietic master regulator RUNX1 is frequently mutated in myeloid and lymphoid malignancies. Analyses of RUNX1 mutations across hematopoietic tissues revealed frequent mutations outside of the N-terminal DNA binding domain. The vast majority of these C-terminal mutations were found to be nonsense and frameshifts resulting in truncated protein products predicted to escape nonsense mediated decay pathways. We modeled this class of truncation mutation using the pathogenic RUNX1 R320* mutation found in both germline and sporadic hematological disease. Homozygous knock-in of RUNX1 R320* in K562 leukemia cells resulted in a megakaryocytic differentiation block and DNA damage sensitivity phenotypes. Gene expression analysis demonstrated that RUNX1 R320* dysregulated unique gene sets when compared to RUNX1 knockdown in addition to shared genes related to megakaryocyte and platelet function. DNA binding across the genome was examined between RUNX1 wild-type and RUNX1 R320* through ChIP-seq, revealing that RUNX1 R320* differential binding was most enriched at enhancer regions. To detect RUNX1 R320* dysregulated enhancer-promoter (E-P) connections we performed GRID-seq and uncovered extensive remodeling of E-P interactions genome-wide in RUNX1 R320* cells. Furthermore, we uncovered a novel role for FOXK2 at RUNX1 regulated enhancers. Analysis of the well-studied MYC enhancer region demonstrated cooperation between RUNX1 R320* and FOXK2 at hematopoietic MYC enhancers NDME and BENC resulting in the significant upregulation of the MYC oncogene. In conclusion, the truncation of RUNX1 results in impaired megakaryocytic differentiation, unique transcriptional alterations, and remodeling of enhancer-promoter connections in cooperation with FOXK2, together contributing to leukemogenesis.
2024-05-29 | GSE236641 | GEO
Project description:The hematopoietic master regulator RUNX1 is frequently mutated in myeloid and lymphoid malignancies. Analyses of RUNX1 mutations across hematopoietic tissues revealed frequent mutations outside of the N-terminal DNA binding domain. The vast majority of these C-terminal mutations were found to be nonsense and frameshifts resulting in truncated protein products predicted to escape nonsense mediated decay pathways. We modeled this class of truncation mutation using the pathogenic RUNX1 R320* mutation found in both germline and sporadic hematological disease. Homozygous knock-in of RUNX1 R320* in K562 leukemia cells resulted in a megakaryocytic differentiation block and DNA damage sensitivity phenotypes. Gene expression analysis demonstrated that RUNX1 R320* dysregulated unique gene sets when compared to RUNX1 knockdown in addition to shared genes related to megakaryocyte and platelet function. DNA binding across the genome was examined between RUNX1 wild-type and RUNX1 R320* through ChIP-seq, revealing that RUNX1 R320* differential binding was most enriched at enhancer regions. To detect RUNX1 R320* dysregulated enhancer-promoter (E-P) connections we performed GRID-seq and uncovered extensive remodeling of E-P interactions genome-wide in RUNX1 R320* cells. Furthermore, we uncovered a novel role for FOXK2 at RUNX1 regulated enhancers. Analysis of the well-studied MYC enhancer region demonstrated cooperation between RUNX1 R320* and FOXK2 at hematopoietic MYC enhancers NDME and BENC resulting in the significant upregulation of the MYC oncogene. In conclusion, the truncation of RUNX1 results in impaired megakaryocytic differentiation, unique transcriptional alterations, and remodeling of enhancer-promoter connections in cooperation with FOXK2, together contributing to leukemogenesis.
2024-05-29 | GSE236640 | GEO
Project description:The hematopoietic master regulator RUNX1 is frequently mutated in myeloid and lymphoid malignancies. Analyses of RUNX1 mutations across hematopoietic tissues revealed frequent mutations outside of the N-terminal DNA binding domain. The vast majority of these C-terminal mutations were found to be nonsense and frameshifts resulting in truncated protein products predicted to escape nonsense mediated decay pathways. We modeled this class of truncation mutation using the pathogenic RUNX1 R320* mutation found in both germline and sporadic hematological disease. Homozygous knock-in of RUNX1 R320* in K562 leukemia cells resulted in a megakaryocytic differentiation block and DNA damage sensitivity phenotypes. Gene expression analysis demonstrated that RUNX1 R320* dysregulated unique gene sets when compared to RUNX1 knockdown in addition to shared genes related to megakaryocyte and platelet function. DNA binding across the genome was examined between RUNX1 wild-type and RUNX1 R320* through ChIP-seq, revealing that RUNX1 R320* differential binding was most enriched at enhancer regions. To detect RUNX1 R320* dysregulated enhancer-promoter (E-P) connections we performed GRID-seq and uncovered extensive remodeling of E-P interactions genome-wide in RUNX1 R320* cells. Furthermore, we uncovered a novel role for FOXK2 at RUNX1 regulated enhancers. Analysis of the well-studied MYC enhancer region demonstrated cooperation between RUNX1 R320* and FOXK2 at hematopoietic MYC enhancers NDME and BENC resulting in the significant upregulation of the MYC oncogene. In conclusion, the truncation of RUNX1 results in impaired megakaryocytic differentiation, unique transcriptional alterations, and remodeling of enhancer-promoter connections in cooperation with FOXK2, together contributing to leukemogenesis.
2024-05-29 | GSE236638 | GEO
Project description:Runx transcription factors are essential for generating functional T cells starting from the earliest stages in thymic T-development. To evaluate how Runx factors instruct T cell development, we perturbed Runx activities using 1) CRISPR-Cas9, simultaneously deleting two predominant, redundant Runx factors, Runx1 and Runx3, and 2) Runx1-overepxression at a stage before pro-T cells commit to a T cell fate. Then single-cell transcriptome analysis was performed. Runx1/Runx3 knockout (KO) vs. Runx1 overexpression (OE) resulted in contrasting deviations from the normal developmental trajectory. The separation of both perturbation conditions from the controls implied that Runx factors regulate gene networks in individual cells to control separate pathways instead of changing distributions of cells among different stages along the control pathway. Notably, a common core set of genes responded to both KO and OE, in opposite directions. Runx activation target genes were selectively enriched for T-identity program and innate lymphoid cell program genes, whereas inhibition targets were significantly associated with stem/progenitor program and myeloid lineage pathways. Pseudotime inference analysis suggested that Runx perturbations also substantially regulate developmental speed, as Runx KO significantly slowed down developmental progression, whereas Runx1 OE resulted in pronounced acceleration. This interpretation was largely supported by Runx activities regulating key transcription factors involved in establishing distinct gene network modules during T cell development. Indeed, further analysis showed that Runx target genes get combinatorial inputs from these Runx-regulated transcription factors as well as from Runx factors themselves. Together, our data suggest that Runx transcription factors drive early T developmental progression by launching gene expression modules associated with T-identity and innate lymphoid cells through mediating other transcription factor cooperativities.
2023-07-09 | GSE218149 | GEO
Project description:Despite absent expression in normal hematopoiesis, the Forkhead factor FOXC1, a critical mesenchymal differentiation regulator, is highly expressed in ~30% of HOXAhigh AML to confer blocked monocyte/macrophage differentiation. Through integrated proteomics and bioinformatics, we discovered that FOXC1 and RUNX1 interact through Forkhead and Runt domains respectively and cooccupy primed and active enhancers distributed close to differentiation genes. FOXC1 stabilises association of RUNX1, HDAC1 and Groucho repressor TLE3 to limit enhancer activity: FOXC1 knockdown induced loss of repressor proteins, gain of CEBPA binding, enhancer acetylation and upregulation of nearby genes, including KLF2. Furthermore, it triggered genome-wide redistribution of RUNX1, TLE3 and HDAC1 from enhancers to promoters leading to repression of self-renewal genes including MYC and MYB. Our studies highlight RUNX1 and CEBPA transcription factor swapping as a feature of leukemia cell differentiation, and reveal that FOXC1 prevents this by stabilising enhancer binding of a RUNX1/HDAC1/TLE3 transcription repressor complex, to oncogenic effect.
2021-08-08 | PXD027740 | Pride
Project description:The lymphoid branch of the immune defense is composed of innate and adaptive immune cells. Using multiple genetic strategies we demonstrate that in the thymus E2A and HEB act in synergy to establish T cell identity and to suppress the aberrant development of innate lymphoid cells that include ILC2 and LTi-like cells. We found that E2A and HEB induce T cell fate by activating the expression of an ensemble of genes encoding for proteins associated with Notch- and pre-TCR signaling and to promote TCRβ antigen receptor assembly. We show that E2A and HEB act in early T progenitors (ETPs) to establish and maintain a T-lineage specific enhancer repertoire, including regulatory elements associated with the Notch1/3 and Rag1/2 gene loci. Based on these and previous observations we propose that the E-Id protein axis specifies innate versus adaptive lymphoid cell fate.
2017-06-01 | GSE95338 | GEO