HDAC7 regulates genes essential for the function of FoxP3+ regulatory T cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA890656 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21908106.fastq.gz | Fastqsanger.gz | |||
| SRR21908107.fastq.gz | Fastqsanger.gz | |||
| SRR21908108.fastq.gz | Fastqsanger.gz | |||
| SRR21908109.fastq.gz | Fastqsanger.gz | |||
| SRR21908110.fastq.gz | Fastqsanger.gz |
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Project description:This SuperSeries is composed of the SubSeries listed below.
2022-10-17 | GSE215820 | GEO
Project description:Correct B cell identity at each stage of cellular differentiation during B lymphocyte development is critically dependent on a tightly controlled epigenomic landscape. We previously identified HDAC7 as an essential regulator of early B cell development and its absence leads to a drastic block at the pro-B to pre-B cell transition. More recently, we demonstrated that HDAC7 loss in pro-B-ALL in infants associates with a worse prognosis. Here we delineate the molecular mechanisms by which HDAC7 modulates early B cell development. We find that HDAC7 deficiency drives global chromatin de-condensation, histone marks deposition and deregulates other epigenetic regulators and mobile elements. Specifically, the absence of HDAC7 induces TET2 expression, which promotes DNA 5-hydroxymethylation and chromatin de-condensation. HDAC7 deficiency also results in the aberrant expression of microRNAs and LINE-1 transposable elements. These findings shed light on the mechanisms by which HDAC7 loss or misregulation may lead to B cell–based hematological malignancies.
2022-06-27 | GSE171855 | GEO
Project description:Regulatory T (Treg) cells play an indispensable role in immune homeostasis. The development and function of Tregs are dependent on transcriptional factor Foxp3, but how constant expression of Foxp3 is maintained in Tregs is not clear. Here we show that ablation of the conserved non-coding DNA sequence 2 (CNS2) at the Foxp3 locus in mice led to spontaneous lymphoproliferative disease and exacerbation of experimental autoimmune encephalomyelitis (EAE). CNS2 is required for activated Treg cells to maintain elevated Foxp3 expression, which is critical for their suppressor function and lineage stability. Mechanistically, upon TCR stimulation, NFAT binds to both CNS2 and Foxp3 promoter and mediates the interaction between CNS2 and Foxp3 promoter. Our findings demonstrated an essential role for CNS2 in maintaining the stability and function of activated Treg cells and identified NFAT as a key mediator of its function. Gene expression was profiled in T regulatory cells (Treg) in WT and CNS2 knockout mice. CNS2 knockout mice lack a conserved non-coding DNA sequence 2 (CNS2) at the Foxp3 locus. Treg cells were further sorted into Foxp3-high and Foxp3-low populations based on the expression level of Foxp3. mRNA was profiled using RNA-Seq (unstranded, polyA+, SE100) in replicate for each condition
2014-09-04 | E-GEOD-57272 | biostudies-arrayexpress
Project description:Regulatory T cells (Tregs) are responsible for limiting autoimmunity and chronic inflammation. Foxp3 is a transcription factor that acts as a master regulator of Treg development and function. A serendipitous observation led to the realization that a well-characterized Foxp3gfp reporter mouse, which expresses an N-terminal GFP-Foxp3 fusion protein, is a hypomorph that causes profoundly accelerated autoimmune diabetes on a NOD background. Although natural Treg development and in vitro function is not significantly altered in Foxp3gfp NOD and C57BL/6 mice, Treg fitness function in inflammatory environments is perturbed and TGF?-induced Treg development reduced. Foxp3gfpis unable to interact with the histone acetyltransferase Tip60, the histone deacetylase HDAC7, and the Ikaros family zinc finger 4, Eos, which leads to reduced Foxp3 acetylation and enhanced K48-linked polyubiquitylation. Collectively this leads to an altered transcriptional landscape and reduced Foxp3-mediated gene repression, notably at the hallmark IL-2 promoter. Loss of controlled Foxp3-driven epigenetic modification leads to Treg insufficiency that causes autoimmunity in prone environments. 16 samples overall split between 2 genotypes (wild type and Foxp3 knock in) and two cell types (Tregs and Tconv)
2012-12-07 | E-GEOD-35164 | biostudies-arrayexpress
Project description:B lymphocyte development is a complex process tightly controlled at the transcriptional level by the action of networks of transcription factors. The repression of genes from alternative lineages is necessary to ensure the acquisition of the correct B cell identity. However, the mechanisms of transcriptional repression during B cell generation are largely unknown. Here, using a conditional knockout mouse model, we show that the histone deacetylase HDAC7 is essential for B cell development. Early deletion of HDAC7 dramatically blocked B cell development at the pro-B cell stage and gave rise to a severe lymphopenia in peripheral organs. HDAC7-deficient pro-B cells exhibit cell lineage promiscuity, expressing myeloid and T lymphocyte genes. In wild-type B cells HDAC7 is recruited to myocyte enhancer factor 2C (MEFC2) binding sites located at the promoters of macrophage and T lymphocyte genes. Our results demonstrate that HDAC7 is a bona fide transcriptional repressor essential for B cell development.
2016-09-26 | GSE66163 | GEO
Project description:The establishment of proper epigenomic landscape is essential during B lymphocyte development in order to acquire a correct B cell identity at each cellular differentiation stage. We previously identified HDAC7 as a critical regulator of early B cell development. Its absence indeed led to the aberrant activation of inappropriate lineage genes, a reduction of proliferation and an increase in cell apoptosis. More recently, we have demonstrated that HDAC7 loss in infant pro-B-ALL associates with poor prognosis. Here we shed light into the HDAC7-mediated molecular mechanisms during early B cell development. HDAC7 deficiency drives not only the expression of inappropriate lineage genes, but also global chromatin de-condensation and deregulation of epigenetic regulators of DNA methylation and potential damaging elements. Specifically, HDAC7 absence induces the expression of TET2, which promotes DNA 5-hydroxymethylation and aberrant gene activation. HDAC7 deficiency also results in the uncontrolled expression of microRNAs and non-coding elements such as LINE-1 transposable elements. These findings are relevant for the mechanistic explanation of why HDAC7 is affected in multiple B-related hematological malignancies. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed in murine pro-B and pre-B lymphocytes.
2022-06-27 | GSE204672 | GEO
Project description:The establishment of proper epigenomic landscape is essential during B lymphocyte development in order to acquire a correct B cell identity at each cellular differentiation stage. We previously identified HDAC7 as a critical regulator of early B cell development. Its absence indeed led to the aberrant activation of inappropriate lineage genes, a reduction of proliferation and an increase in cell apoptosis. More recently, we have demonstrated that HDAC7 loss in infant pro-B-ALL associates with poor prognosis. Here we shed light into the HDAC7-mediated molecular mechanisms during early B cell development. HDAC7 deficiency drives not only the expression of inappropriate lineage genes, but also global chromatin de-condensation and deregulation of epigenetic regulators of DNA methylation and potential damaging elements. Specifically, HDAC7 absence induces the expression of TET2, which promotes DNA 5-hydroxymethylation and aberrant gene activation. HDAC7 deficiency also results in the uncontrolled expression of microRNAs and non-coding elements such as LINE-1 transposable elements. These findings are relevant for the mechanistic explanation of why HDAC7 is affected in multiple B-related hematological malignancies. Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for histone modifications H3K27ac and H3K27me3 in murine pro-B lymphocytes.
2022-06-27 | GSE204673 | GEO
Project description:B lymphopoiesis is the result of several cell lineage choices and differentiation steps whose perturbation leads to B cell malignancies. Cellular transitions for B cell generation have been associated with gene activation and silencing by networks of B cell specific transcription factors (TFs) and dynamic changes in DNA methylation. How gene repression is established and which lineage-specific transcriptional repressors are involved during B cell lymphopoiesis are still not totally understood. Here, by using our in vivo experimental approach, we have found that HDAC7 represses Tet2 enzyme in pro-B cells. In fact, HDAC7 deficient pro-B cells show a significant increase in the percentage of global 5-hydroxymethylation. To prove the role of HDAC7 in 5-hydroxymethylation, we have performed a genome-wide experimental approach. hMeDIP-sequencing experiments reveal an increase in the enrichment of this epigenetic modification at many loci related to lineage inappropriate genes. Our results corroborate that HDAC7 is an essential transcriptional regulator during early B cell development that silences lineage or functionally inappropriate genes and unveil an unexpected role of a class IIa HDAC in controlling DNA methylation
2022-06-28 | GSE135263 | GEO
Project description:The proposed use of Foxp3+ T-regulatory (Treg) cells as potential cellular therapy in patients with autoimmune diseases, or post-hemopoietic stem cell or organ transplantation, requires a sound understanding of the transcriptional regulation of Foxp3 expression. Conserved CpG dinucleotides in the Treg-specific demethylated region (TSDR) upstream of Foxp3 are demethylated only in stable, thymic-derived Foxp3+ Tregs. Since methyl-binding domain (Mbd) proteins recruit histone-modifying and chromatin-remodeling complexes to methylated sites, we tested whether targeting of Mbd2 might promote demethylation of Foxp3 and thereby promote Treg numbers or function. Surprisingly, while ChIP analysis showed Mbd2 binding to the Foxp3-associated TSDR site in Tregs, Mbd2 targeting by homologous recombination or siRNA decreased Treg numbers and impaired Treg suppressive function in vitro and in vivo. Moreover, we found complete TSDR demethylation in WT Tregs but >75% methylation in Mbd2-/- Tregs, whereas re-introduction of Mbd2 into Mbd2-null Tregs restored TSDR demethylation, Foxp3 gene expression and Treg suppressive function. Lastly, Mbd2-/- Tregs had markedly binding of the DNA demethylase enzyme, Tet2, in the TSDR region. These data show that Mbd2 has a key role in promoting TSDR demethylation, Foxp3 expression and Treg suppressive function. RNA from three independent samples from magnetically separated CD4+CD25+ Treg of MBD2–/– mice, compared to wild type control (all Balb/c background).
2013-09-01 | E-GEOD-48653 | biostudies-arrayexpress
Project description:Regulatory T cells (Tregs) are responsible for limiting autoimmunity and chronic inflammation. Foxp3 is a transcription factor that acts as a master regulator of Treg development and function. A serendipitous observation led to the realization that a well-characterized Foxp3gfp reporter mouse, which expresses an N-terminal GFP-Foxp3 fusion protein, is a hypomorph that causes profoundly accelerated autoimmune diabetes on a NOD background. Although natural Treg development and in vitro function is not significantly altered in Foxp3gfp NOD and C57BL/6 mice, Treg fitness function in inflammatory environments is perturbed and TGFβ-induced Treg development reduced. Foxp3gfpis unable to interact with the histone acetyltransferase Tip60, the histone deacetylase HDAC7, and the Ikaros family zinc finger 4, Eos, which leads to reduced Foxp3 acetylation and enhanced K48-linked polyubiquitylation. Collectively this leads to an altered transcriptional landscape and reduced Foxp3-mediated gene repression, notably at the hallmark IL-2 promoter. Loss of controlled Foxp3-driven epigenetic modification leads to Treg insufficiency that causes autoimmunity in prone environments.
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