Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA695260 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13563876.fastq.gz | Fastqsanger.gz | |||
| SRR13563877.fastq.gz | Fastqsanger.gz | |||
| SRR13563878.fastq.gz | Fastqsanger.gz | |||
| SRR13563879.fastq.gz | Fastqsanger.gz | |||
| SRR13563880.fastq.gz | Fastqsanger.gz |
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Project description:The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper.
| S-EPMC8105723 | biostudies-literature
Project description:Using CITE-seq we measured expression of 132 proteins on the cell surfaces of single human bone marrow aspirate cells. Expression of each protein was normalized with a isotype-specific control on a single cell basis. Principal compenent analysis of normalized proteins was used to produce UMAP plots that clustered like cell types. After identifying pro-B cells on UMAP plots and further refining these populations by filtering on CD19 expression and absent CD20/IgM expression, we identified differentially expressed genes between patient and control pro-B cells.
2021-03-31 | GSE165645 | GEO
Project description:A major problem with linking transcription factor binding to function is that many factors bind to a large number of, at least in any given cell type, seemingly irrelevant regions. This makes it hard to filter out which binding sites are responsible for the regulation of a given gene. PU.1 (Spi1, Sfpi1) is an excellent example of a transcription factor that works both to mediate developmental choices and to serve the alternative developmental fates that emerge from these choices. Its role in T-cell development is confined to the early stages where high PU.1 expression persists through multiple cell divisions and is sharply downregulated over the DN2a-to-DN2b T-cell commitment stage. Even though it is known that PU.1 is necessary for the survival of the earliest T-cell progenitors, where it is needed for optimal proliferation, control of alternative lineage genes, and correct timing of the access to T-lineage genes, it has not been well-studied how PU.1 finds it targets and exerts its functions within this context. Here, we show in detail how PU.1 selects its binding sites and subsequently regulate gene expression. We show that PU.1 has two effective affinity thresholds for occupancy depending on current chromatin openness as measured by ATAC-sequencing, but that it is easily capable of binding sites in closed chromatin. Unexpectedly, although its binding to promoters is least constrained, promoters are the only major class of sites where it exerts a predominantly negative effect; otherwise it works locally as an activator, mainly mediated through binding to sites in closed or dynamically closing distal enhancer elements, where it can rapidly open chromatin and induce histone acetylation. However, its ability to open the chromatin depends not only on its own affinity but also on the presence of collaborating factors, because we show that PU.1 introduction into PU.1-negative cells triggers a massive reorganization of occupancy patterns of at least three other factors: Runx1, Satb1, and Gata3. Most strikingly, PU.1’s “theft” of Runx1 and Satb1 from many sites where they were binding in the absence of PU.1 enables PU.1 to exert a novel form of repression even on genes where it has no binding sites itself. We show here that PU.1 requires domains outside of its DNA binding domain to properly open chromatin, and this structural requirement is directly connected with its ability to bind to Runx1 and to Satb1, and moreover, Runx1, in particular, is an important collaborator to activate many of its target genes in the context of early T-cell development. Thus, PU.1 regulates gene expression via two distinct mechanisms. First, PU.1 steals Satb1 and Runx1 from many genomic sites, thereby repressing T cell gene expression indirectly. Second, PU.1, opens chromatin, recruits Satb1 and Runx1 to new sites, and directly activates its target gene expression. In summary, we here present a model where a transcription factor can work through redeployment of other factors and not only through sites that it binds itself.
2018-06-21 | GSE93755 | GEO
Project description:To investigate the effects of DB2115 (PU.1 binding-site inhibitor/redistributor) upon PU.1 genomic localization, the transcriptome and chromatin accessibility.
2024-07-31 | GSE267384 | GEO
Project description:To investigate the effects of DB2115 (PU.1 binding-site inhibitor/redistributor) upon PU.1 genomic localization, the transcriptome and chromatin accessibility.
2024-07-31 | GSE267383 | GEO
Project description:Chromatin accessibility in C. albicans stimulated HoxER-PU.1 WT and HoxER-PU.1 KO neutrophils and DMSO, TSA or Entinostat treated HoxER-PU.1 WT neutrophils
| PRJNA434709 | ENA
Project description:Neutrophils are essential first line defense cells against invading pathogens, yet their inappropriate activation contributes to immunological diseases and can cause collateral tissue damage. However, if and how neutrophils cell-intrinsically titrate their inflammatory response remains unknown. Here, we conditionally deleted PU.1, a key myeloid transcription factor, from the neutrophils of mice undergoing fungal infection, and then performed comprehensive epigenomic profiling. We find that a major function of PU.1 is to restrain the neutrophils’ immune response by broadly suppressing genomic enhancer outputs via recruiting histone deacetylase activity, thereby limiting the immune-stimulatory AP1-transcription factor JUNB from entering chromatin. Thus, neutrophils rely on a direct PU.1 repressor function as rheostat of the inflammatory chromatin state, safeguarding their epigenome from undergoing uncontrolled activation prior to pathogenic stimulation.
2019-03-19 | GSE110860 | GEO
Project description:We used the myelogenous leukemia line K562 as a model of HDACi-induced differentiation to investigate chromatin accessibility (DNase-seq) and expression (RNA-seq) changes associated with this process. We identified several thousand specific regulatory elements (~10% of total DHS sites) that become significantly more or less accessible with sodium butyrate or suberanilohydroxamic acid (SAHA) 72-hour treatments. Most of the differential DNase-hypersensitive (DHS) sites display hallmarks of enhancers; including being enriched for non-promoter regions, associated with nearby gene expression changes, and capable of increasing luciferase reporter expression in K562 cells. Differential DHS sites were enriched for key hematopoietic lineage transcription factor motifs, including SPI1 (PU.1), a known pioneer factor. We found PU.1 becomes up-regulated and increases binding at opened DHS sites by ChIP-seq with HDACi treatment, but show that increased PU.1 protein levels alone are sufficient for only modest increases in chromatin accessibility. PU.1 knockdown by shRNA failed to block the HDACi-induced chromatin accessibility and expression changes in K562, suggesting factors other than PU.1 are responsible for establishment of active enhancers in the HDACi induced differentiation process.
2016-04-10 | GSE74999 | GEO
Project description:PU.1 is a prototype master transcription factor (TF) of hematopoietic cell differentiation with diverse roles in different lineages. Analysis of its genome-wide binding pattern across PU.1 expressing cell types revealed manifold cell type-specific binding patterns. They are not consistent with the epigenetic and chromatin constraints to PU.1 binding observed in vitro, suggesting that PU.1 requires auxiliary factors to access DNA in vivo. Using a model of transient mRNA expression we show that PU.1 induction leads to the extensive remodeling of chromatin, redistribution of partner transcription factors and rapid initiation of a myeloid gene expression program in heterologous cell types. By probing PU.1 mutants for defects in chromatin access and screening for PU.1 proximal proteins in vivo, we found that its N-terminal acidic domain was required for the recruitment of SWI/SNF remodeling complexes, de novo chromatin access and stable binding as well as the redistribution of partner TFs.
2019-11-20 | PXD013167 | Pride