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Genome-scale analysis in blood progenitor and mast cells reveals how lineage-affiliated transcription factors control distinct regulatory programs [Beadchip Experiments #2]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE55244 | GEO | 2014/04/24

SECONDARY ACCESSION(S): PRJNA238990

REPOSITORIES: GEO

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Genome-scale analysis in blood progenitor and mast cells reveals how lineage-affiliated transcription factors control distinct regulatory programs [Beadchip Experiments]

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. Total RNA from primary mast cells transfected with retroviral shRNA vectors were compared to negative controls (shRNA against luciferase).

2014-04-24 | E-GEOD-47988 | biostudies-arrayexpress

Genome-scale analysis in blood progenitor and mast cells reveals how lineage-affiliated transcription factors control distinct regulatory programs [Beadchip Experiments #2]

2014-04-24 | E-GEOD-55244 | biostudies-arrayexpress

Genome-scale analysis in blood progenitor and mast cells reveals how lineage-affiliated transcription factors control distinct regulatory programs [ChIP-Seq/RNA-Seq Experiments]

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

Genome-scale analysis in blood progenitor and mast cells reveals how lineage-affiliated transcription factors control distinct regulatory programs [Beadchip Experiments]

2014-04-24 | GSE47988 | GEO

Genome-scale analysis in blood progenitor and mast cells reveals how lineage-affiliated transcription factors control distinct regulatory programs [ChIP-Seq/RNA-Seq Experiments]

2014-04-24 | GSE48085 | GEO

Lineage-specific Protein Interactomes of the Hox Transcription Factor Ubx revealed by Close-Proximity Protein Biotinylation

Project description:Cell type diversity is controlled by transcription factors (TFs), which regulate specific yet flexible gene expression programs depending on the cellular environment. However, how sets of TFs work together to promote such diversity with high precision is still unknown. We used the Hox TF Ultrabithorax (Ubx) as a model because of its essential functions in multiple cell types. Assuming that functional diversity emerges from specifc protein interactions in different cell types, we explored Ubx protein interactomes in three different tissue lineages in vivo. Using proximity dependent Biotin IDentification (BioID) in Drosophila embryos, we find that Ubx interacts with largely non-overlapping sets of proteins in each tissue lineage. Intriguingly, this specificity does not primarily result from Ubx binding to proteins with lineage-restricted functions. Instead, Ubx interacts in a lineage-specific manner with ubiquitously expressed subunits of proteins complexes controlling general aspects of gene expression, like chromatin remodelling or RNA processing. Thus, our work reveals that cell type-specific protein interaction networks not necessarily involve cell type-specific partners and that the function of key TFs may extend to the control over the entire realm of gene expression, including splicing and translation. These findings challenge two central dogmas in cell lineage specification, namely the strong reliance on differential RNA expression as a measure for specificity determinants and the enhancer-centric approach to understand gene regulation.

2020-04-22 | PXD014481 | Pride

Human connective tissue mast cell proteome

Project description:Mast cells are hematopoietic cells that reside preferentially in tissues exposed to internal and external environments. Mast cells sense immunological, inflammatory and environmental stimuli, and can be activated to release granules and generate inflammatory mediators. Mast cell-derived products confer protection against snake venoms and some parasite infections. Aberrant activation of mast cells is a major contributor to human pathology, including allergy, asthma and adverse drug reactions. Their strict tissue location has largely impeded the isolation of large numbers of primary mast cell for further analysis. To better understand the biology of mast cells, we analyzed the proteome of primary human and mouse mast cells by quantitative mass spectrometry. We identified a mast cell-specific protein signature that was conserved from mouse to man. Compared to a comprehensive set of other immune cell lineages, proteome analysis identified a unique and distant mast cell cluster. The mast cell signature included proteins governing granule biosynthesis and secretion, as well as proteoglycan- and neurotransmitter metabolism. Proteome conservation across species suggests evolutionary maintenance of mast cell functions.

2020-02-12 | PXD014978 | Pride

Transcription factors harbor functional RNA-binding domains

Project description:Transcription factors (TFs) orchestrate the gene expression programs that define each cell’s identity, and the canonical TF accomplishes this with two functional domains1–7. The DNA-binding domain interacts with specific genomic sequences, and the effector domain binds coactivators or co-repressors that contribute to transcriptional regulation. We report here that TFs also frequently contain an RNA-binding domain and that this also contributes to gene regulation. Nearly half of TFs in human cells show evidence of RNA-binding and their affinities for RNA are similar to those of well-studied RNA-binding proteins. The RNA-binding sites of TFs have sequence and functional features analogous to the arginine-rich motif of the HIV transcriptional activator Tat8,9. RNA-binding contributes to TF function by promoting the dynamic association of TFs with chromatin. We conclude that the canonical definition of transcription factors is incomplete, and that the ability of many TFs to bind DNA, RNA and protein is fundamental to gene regulation.

2023-07-02 | PXD035484 | Pride

Synovial microenvironment-influenced mast cells promote the progression of rheumatoid arthritis

Project description:Mast cells are phenotypically and functionally highly heterogeneous, and their state is possibly controlled by their local microenvironment. Therefore, concrete analyses are needed to understand whether mast cells act as powerful motivators or dispensable bystanders in specific diseases. Here, we evaluated the correlation between synovial mast cells and rheumatoid arthritis (RA) disease severity, and the efficacy of therapeutic interventions against mast cells. We showed that degranulation of mast cells in inflammatory synovial tissues of RA patients was induced via MAS-related G protein-coupled receptor X2 (MRGPRX2), and the expression of MHC class II (MHC II) and costimulatory molecules on mast cells were upregulated. These unique signaling response led to mast cell activation and promoted T cell responses, resulting in the progression of RA. Collagen-induced arthritis mouse models treated with a combination of anti-IL-17A and cromolyn sodium, a mast cell membrane stabilizer, showed significantly reduced clinical severity and decreased bone erosion. The findings of the present study suggest that synovial microenvironment-influenced mast cells contribute to RA and may provide a novel mast cell-targeting therapy for RA.

2024-01-07 | PXD038584 | Pride

Surprising mechanisms and regulatory roles of yeast transcription factors [ChIP-seq]

Project description:DNA sequence-specific transcription factors (TFs) modulate transcription and chromatin architecture, acting from regulatory sites in enhancers and promoters of eukaryotic genes. How multiple TFs cooperate to regulate individual genes is still unclear. Most yeast TFs are thought to regulate transcription via binding to Upstream Activating Sequences, situated within a few hundred base pairs upstream of the regulated gene1. While this model has been validated for individual TFs and specific genes, it has not been tested in a systematic way. We integrated information on the binding and expression targets for the near-complete set of yeast TFs. Here we show that, contrary to expectations, there are few TFs with dedicated activator or repressor functions with most TFs having a dual role. While nearly all protein coding genes are regulated by one or more TFs, our analysis revealed limited overlap between TF binding and gene regulation. Rapid depletion of many TFs also revealed numerous regulatory targets distant from detectable TF binding sites, suggesting unexpected regulatory mechanisms. Our study provides a comprehensive survey of TF functions, offering insights into interactions between the set of TFs expressed in a single cell type and how they contribute to the complex program of gene regulation.

2023-08-01 | GSE236945 | GEO

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