Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA238990 | ENA |
REPOSITORIES: ENA
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Project description:Genome-scale analysis in blood progenitor and mast cells reveals how lineage-affiliated transcription factors control distinct regulatory programs [Beadchip Experiments]
| PRJNA208547 | ENA
Project description:Genome-scale analysis in blood progenitor and mast cells reveals how lineage-affiliated transcription factors control distinct regulatory programs [ChIP-Seq/RNA-Seq Experiments]
| PRJNA208892 | ENA
Project description:In development, pioneer transcription factors access silent chromatin to reveal lineage-specific gene programs. The structured DNA-binding domains of pioneer factors have been well characterized, but whether and how low-complexity intrinsically disordered regions (IDRs) affect chromatin and control cell fate is unclear. Here, we report deletion of an IDR of the pioneer factor TCF-1, termed “L1”, leads to an early developmental block in T cells. The few T cells that develop from progenitors expressing TCF-1 lacking L1 exhibit lineage infidelity distinct from the lineage diversion of TCF-1 deficient cells. Mechanistically, L1 is required for activation of T cell genes and de-repression of GATA2 driven genes, normally reserved to the mast cell and dendritic cell lineages. Underlying this lineage diversion, L1 mediates binding of TCF-1 to its earliest target genes which are subject to repression as T cells develop. These data suggest TCF-1’s intrinsically disordered N-terminus maintains T cell lineage fidelity.
2024-06-16 | PXD043586 | Pride
Project description:The myeloid innate immune system plays key roles in the defence against parasites and bacteria, and carries out essential functions during tissue homeostasis and repair. It consist of neutrophils, macrophages, eosinophils, basophils and mast cells. Myelopoietic dysfunction or deregulation underlies numerous pathologies, ranging from immune deficiencies and allergies to myeloproliferative disorders and myeloid leukemia. To study malignant myelopoiesis, it is essential to understand the ontology of the different celltypes. In a generally accepted model for hematopoietic differentiation, all myeloid cells are preceded by a common granulocyte and macrophage progenitor that has the potential for all myeloid celltypes at the single cell level. However, we recently proposed a model for mouse hematopoiesis in which myeloid cells are formed via two independent pathways, one leading towards macrophages and neutrophils and one leading towards eosinophils, basophils and mast cells. The first pathway is affiliated with lymphoid potentials whereas the latter with megakaryocyte/erythroid development. Here, we demonstrate that those findings translate to human hematopoiesis. We demonstrate prospective isolation of myeloid progenitor cells that have restricted multipotent myeloid potential and are affiliated with lineages similar to those found in the mouse hierarchy.
2019-03-27 | GSE113046 | GEO
Project description:The emerging notion of hematopoietic stem- and progenitor cells (HSPCs) as a low-primed cloud without sharply demarcated gene expression programs raises the question on how cellular fate options emerge, and at which stem-like stage lineage priming is initiated. Here we investigated single-cell chromatin accessibility of Lineage-, cKit+, Sca1+ (LSK) HSPCs spanning the early differentiation landscape. Application of a signal-processing algorithm to detect transition points corresponding to massive alterations in accessibility of 521 transcription factor-motifs revealed a population of LSK FMS-like tyrosine kinase 3(Flt3)intCD9high cells that concurrently display stem-like and lineage-affiliated chromatin signatures pointing to simultaneous gain of both Lympho-Myeloid and Megakaryocyte-Erythroid programs. Molecularly and functionally, these cells position between stem cells and committed progenitors, display multi-lineage capacity in vitro and in vivo, but lack self-renewal activity. This integrative molecular analysis resolves the heterogeneity of cells along hematopoietic differentiation trajectories, and permits investigation of chromatin-mediated transition between multipotency and lineage restriction.
2022-05-02 | GSE148746 | GEO
Project description:Despite major advances in the generation of genome-wide binding maps, the mechanisms by which transcription factors (TFs) regulate cell type identity have remained largely obscure. Through comparative analysis of 10 key haematopoietic TFs in both mast cells and blood progenitors, we demonstrate that the largely cell-type specific binding profiles are not opportunistic, but instead contribute to cell-type specific transcriptional control, because (1) mathematical modelling of differential binding of shared TFs can explain differential gene expression, (2) cell-type specific binding is largely mediated through consensus binding sites, and (3) knock-down of blood stem cell regulators Gata2 and Erg in mast cells reveals mast cell specific genes as direct targets. Finally we show that the known mast cell regulators Mitf and c-Fos likely contribute to the global reorganisation of TF binding profiles. Taken together therefore, our study elucidates how key regulatory TFs contribute to transcriptional programmes in several distinct mammalian cell types. Comparison of HPC7 cell line (haematopoietic multipotent progenitor) and primary mast cells. 10 key haematopoietic transcription factors and mRNA expression were profiled in both cell types.
2014-04-24 | E-GEOD-48085 | biostudies-arrayexpress
Project description:Blood cell formation is a tightly regulated process initiated from a rare population of multipotent hematopoietic stem cells. Subsequent differentiation proceeds in a hierarchical manner with the generation of intermediate progenitor cells, in which alternative lineage potentials become gradually restricted. A deeper understanding of these events is crucial not only to understand normal blood cell formation, but also for leukemia, where a defining feature is inappropriate differentiation. Here, we identified Hepatic Leukemia Factor (Hlf) as being highly and selectively expressed in primitive multipotent hematopoietic stem and progenitors. We demonstrate that Hlf is a strong negative regulator of B-, NK- and T cell development and instructs multipotent progenitors to adopt a myeloid fate in a cell autonomous manner; phenotypes underwritten by the induction of myeloid affiliated transcriptional programs, the concomitant ablation of lymphoid gene programs and a genome-wide binding spectra that involved active enhancers of myeloid-competent cells. Collectively, our studies establish Hlf as a key regulator of the earliest lineage-commitment events at the transition from multipotency to lineage-restricted progeny, with implications for both normal and malignant hematopoiesis. Gene expression profiling of control or Hlf/Hlf lentivirus infected GMLPs (2 replicates per group) and Hlf inducible GMLPs maintained for 4 days on OP9 stroma in the presence or absence of doxycycline (2 replicates per group)
2016-06-12 | E-GEOD-69858 | biostudies-arrayexpress
Project description:To determine the function of Camkk2 in HSC we performed a microarray analysis on isolated KSL from WT and Camkk2 null mice. Using a threshold of 0.05 for statistical significance (p-value) and a log fold change of expression with absolute value of at least 0.6, 1831 differentially expressed genes (DEGs) were identified out of a total of 29352 genes with measured expression. When compared to WT KSL, 1289 genes were significantly downregulated and 533 genes were upregulated in Camkk2 null HSC. The genes downregulated in Camkk2 null KSL were strongly enriched in HSC, early progenitors and lymphoid-myeloid-affiliated genes (s-myly) primed in HSC. Of note, HSC-affiliated genes found downregulated in Camkk2 KSL included Hlf, Meis1, Pbx-1 and Prdm5 which are 4 of the 8 genes capable to reprogram committed murine blood cells into HSC. The GSEA analysis also showed that genes affiliated with the late progenitor signature and erythroid genes primed in HSC and GMP specific genes (d-my) were significantly upregulated in Camkk2 null KSL. These findings indicate Camkk2 controls crucial transcriptional programs involved in the mechanism of HSC differentiation and lineage commitment.
2018-02-13 | GSE95733 | GEO