Effect of BCL11B overexpression on transcriptome of T-cell acute lymphoblastic leukemia (T-ALL) cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE84675 | GEO | 2017/03/06
SECONDARY ACCESSION(S): PRJNA330819
REPOSITORIES: GEO
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Project description:Epigenetic landscapes can provide insight into regulation of gene expression and cellular diversity. Here, we examined the transcriptional and epigenetic profiles of seven human blood NK cell populations, including adaptive NK cells. The BCL11B gene, encoding a transcription factor (TF) essential for T cell development and function, was the most extensively regulated, with expression increasing throughout NK cell differentiation. Several Bcl11b-regulated genes associated with T cell-signaling were specifically expressed in adaptive NK cell subsets. Regulatory networks revealed reciprocal regulation at distinct stages of NK cell differentiation, with Bcl11b repressing RUNX2 and ZBTB16 in canonical and adaptive NK cells, respectively. A critical role for Bcl11b in driving NK cell differentiation was corroborated in BCL11B mutated patients and by ectopic Bcl11b expression. Moreover, Bcl11b was required for adaptive NK cell responses in a murine CMV model, supporting expansion of these cells. Together, we define the TF regulatory circuitry of human NK cells and uncover a critical role for Bcl11b in promoting NK cell differentiation and function.
2021-05-28 | GSE162472 | GEO
Project description:T-cell receptor (TCR) signals play a critical role in guiding selected thymocytes to distinct lineages by activating genes for transcription factors, such as ThPOK and Runx3, for the helper- or cytotoxic-lineage, respectively. Here we show that Bcl11b, known as an early T-lineage commitment factor, is essential for proper expression of ThPOK and Runx3. Loss of Bcl11b resulted in premature and random expression of these specification factors, leading to lineage scrambling that was disconnected from TCR restriction by MHC. Early Thpok repression by Bcl11b is independent of its known transcriptional silencer, but requires the C-terminal zinc-finger of Bcl11b. Collectively, our findings shed new light on the role of Bcl11b in priming lineage-specifying genes to integrate TCR signals into a subsequent developmental program that dissects effector lineages.
2017-07-20 | GSE90949 | GEO
Project description:During T cell development, multipotent progenitors relinquish competence for other fates and commit to the T cell lineage by turning on Bcl11b, which encodes a transcription factor. To clarify lineage commitment mechanisms, we followed developing T cells at the single-cell level using Bcl11b knock-in fluorescent reporter mice. Notch signaling and Notch activated transcription factors collaborate to activate Bcl11b expression irrespectively of Notch-dependent proliferation. These inputs work via three distinct, asynchronous mechanisms: an early locus âpoisingâ function dependent on TCF-1 and GATA-3, a stochastic-permissivity function dependent on Notch signaling, and a separate amplitude-control function dependent on Runx1, a factor already present in multipotent progenitors. Despite their necessity for Bcl11b activation, these inputs act in a stage specific manner, providing a multitiered mechanism for developmental gene regulation. Two sets of samples were generated from DN T-cell sub-populations derived from culture of bone marrow progenitors from mice containing a knock-in Bcl11b-YFP reporter
2016-06-27 | E-GEOD-76606 | biostudies-arrayexpress
Project description:This study identified a cytogenetic-molecular entity, we named BCL11B-R, that showed a typical constellation of genomic features, namely BCL11B activation via chromosome translocations at 14q32, a distinct transcriptome profile, and FLT3 mutations.
2021-09-05 | GSE162282 | GEO
Project description:To investigate the role of BCL11B in the initial stages of human thymopoiesis, we performed loss of function (knockdown) studies in an in vitro human thymopoiesis model (cord blood CD34+ cells co-cultured on OP9DLL1 stromal cell line). Gene expression profiling by RNA-Seq demonstrated that BCL11B knockdown resulted in downregulation of T-lineage genes and upregulation of stem cell, myeloid and NK genes, indicating BCL11B is required for the establishment of a T-lineage commitment transcriptional program.
2017-03-06 | GSE93902 | GEO
Project description:Notch-dependent BCL11B induction converts thymus seeding precursor cells into committed T cell progenitors that subsequently differentiate into T cells bearing either the γδ or αβ T cell receptor. In human, strong Notch activation favors γδ T cell development at the expense of αβ-lineage differentiation, but the underlying molecular mechanism has remained unclear. Therefore, we performed paired mRNA and miRNA profiling across 11 stages of human T cell development, including developing γδ T cells. We identify the miR-17-92 cluster as a direct Notch target and show that miR-17 promotes human TCRγδ T cell development by targeting BCL11B, a gene required for αβ but not for γδ T cell development. Thus, following its role as a licensing factor to induce BCL11B expression in early T cell precursors, Notch activation limits BCL11B expression through miR-17 until thymocytes have passed the β-selection checkpoint when Notch activation is turned off. Hereby Notch prevents premature BCL11B upregulation that is required for αβ-lineage differentiation and this results in preferential γδ-lineage differentiation. Our work unravels a dual role for Notch in controlling BCL11B expression during intrathymic differentiation and provides a unique resource for understanding the mRNA/miRNA interactions that control human T cell development. We used microarrays in order to profile gene expression in CD34+ thymocytes before culture and after 5 or 10 days culture on OP9 stromal cells expressing Notch ligands JAG1, JAG2, DLL1 or DLL4.
2020-05-26 | GSE129853 | GEO
Project description:Notch-dependent BCL11B induction converts thymus seeding precursor cells into committed T cell progenitors that subsequently differentiate into T cells bearing either the γδ or αβ T cell receptor. In human, strong Notch activation favors γδ T cell development at the expense of αβ-lineage differentiation, but the underlying molecular mechanism has remained unclear. Therefore, we performed paired mRNA and miRNA profiling across 11 stages of human T cell development, including developing γδ T cells. We identify the miR-17-92 cluster as a direct Notch target and show that miR-17 promotes human TCRγδ T cell development by targeting BCL11B, a gene required for αβ but not for γδ T cell development. Thus, following its role as a licensing factor to induce BCL11B expression in early T cell precursors, Notch activation limits BCL11B expression through miR-17 until thymocytes have passed the β-selection checkpoint when Notch activation is turned off. Hereby Notch prevents premature BCL11B upregulation that is required for αβ-lineage differentiation and this results in preferential γδ-lineage differentiation. Our work unravels a dual role for Notch in controlling BCL11B expression during intrathymic differentiation and provides a unique resource for understanding the mRNA/miRNA interactions that control human T cell development. We used microarrays in order to profile the gene expression in 11 ex vivo T cell subsets, isolated from human thymus. Cord blood CD34+Lin- HPCs were used as a reference subset for extrathymic HPCs.
2020-05-26 | GSE129852 | GEO
Project description:Notch-dependent BCL11B induction converts thymus seeding precursor cells into committed T cell progenitors that subsequently differentiate into T cells bearing either the γδ or αβ T cell receptor. In human, strong Notch activation favors γδ T cell development at the expense of αβ-lineage differentiation, but the underlying molecular mechanism has remained unclear. Therefore, we performed paired mRNA and miRNA profiling across 11 stages of human T cell development, including developing γδ T cells. We identify the miR-17-92 cluster as a direct Notch target and show that miR-17 promotes human TCRγδ T cell development by targeting BCL11B, a gene required for αβ but not for γδ T cell development. Thus, following its role as a licensing factor to induce BCL11B expression in early T cell precursors, Notch activation limits BCL11B expression through miR-17 until thymocytes have passed the β-selection checkpoint when Notch activation is turned off. Hereby Notch prevents premature BCL11B upregulation that is required for αβ-lineage differentiation and this results in preferential γδ-lineage differentiation. Our work unravels a dual role for Notch in controlling BCL11B expression during intrathymic differentiation and provides a unique resource for understanding the mRNA/miRNA interactions that control human T cell development. The expression of 756 miRNAs was determined using the Taqman stem-loop RT-qPCR method as previously described (Mets E. Leukemia. 2015, Mavrakis KJ. Nat Genet. 2011).
2020-05-26 | GSE129855 | GEO
Project description:Type-2 innate lymphoid cells (ILC2s) promote anti-helminth responses and contribute to allergies. Though Bcl11b has been previously considered a T-lineage identity transcription factor (TF) that restrains the innate-cell genetic programs, we report here that Bcl11b is highly expressed in mature ILC2s and acts upstream of the key ILC2 TFs Gfi1, Gata-3, and of IL-33 receptor IL1rl1 (T1ST2). Additionally, Bcl11b-/- ILC2s de-repressed Rorγt, Ahr and IL-23 receptor, normally expressed in type-3 ILCs (ILC3s). Consequently, Bcl11b-/- ILC2s lost ILC2 functions and gained ILC3 functions, expanding in response to the protease allergen papain, however producing IL-17 and IL-22, and not IL-5 and IL-13, causing lung neutrophilia rather than eosinophilia, and diminished mucus production. Our results broaden Bcl11b's role from a T-cell only TF, and establishes that Bcl11b sustains mature ILC2 genetic and functional programs and lineage fidelity through positive regulation of essential ILC2 TFs and negative regulation of pivotal ILC3 TFs. RNA-seq analysis on sorted ILC2s from the mLNs of Bcl11bF/F Cre-ERT2 and wildtype mice at steady state following tamoxifen mediated deletion of Bcl11b
2015-07-28 | E-GEOD-67437 | biostudies-arrayexpress
Project description:Transcriptional profiling of mouse iNKT cells comparing wild type and Bcl11b deficient cell. The mice were treated with 4 μg of α-galactosylceramide. Goal was to determine the effects of transcription factor Bcl11b removal in iNKT cells. Intraperitoneal treatment with 4 μg of α-Galactosylceramide. Two pair of wild type (BCL11b F/F Vα14 transgenic) and Knock out (BCL11b F/F PLZF-Cre Vα14 transgenic)) mice were treated. Lymphocytes from spleen and liver were enriched and stain with PBS-57 Loaded CD1d tetramer. Pure iNKT cells were collected through cell sorter.
2016-08-10 | E-GEOD-73679 | biostudies-arrayexpress