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Effector regulatory T cell differentiation and immune homeostasis depend on the transcription factor Myb

ABSTRACT: FoxP3-expressing regulatory T (Treg) cells are essential to maintain immune homeostasis. Activated Treg cells undergo further differentiation into an effector state that highly express genes critical for Treg cell function. Here we demonstrate that mice lacking the transcription factor Myb in Treg cells succumb to a multi-organ inflammatory disease. Myb was specifically expressed in, and required for the differentiation of, thymus-derived effector Treg cells. The combination of transcriptome and DNA binding analyses revealed that Myb directly regulates a large proportion of the effector Treg cell specific gene expression in mouse and human cells. This study identifies a critical role for Myb in the gene regulatory network controlling effector Treg cell differentiation and function.

ORGANISM(S): Mus musculus

PROVIDER: GSE72494 | GEO | 2017/01/01

SECONDARY ACCESSION(S): PRJNA294161

REPOSITORIES: GEO

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The transcription factor Myb enhances CD8+ T cell stemness and antitumor immunity

Project description:Stem cells are maintained by transcriptional programs promoting self-renewal and repressing differentiation. Here, we show that the transcription factor Myb is essential for generating and maintaining stem cells within the CD8+ T-cell memory compartment. We found that, following viral infection, CD8+ T cells lacking Myb underwent terminal differentiation and exhibited impaired capacity to form CD62L+ stem cell-like memory cells. Myb acted both as a transcriptional activator of Tcf7 to enhance the development of memory cells and as a repressor of effector differentiation through Zeb2 suppression. Myb mutants’ complementation revealed that the Myb transactivation domain was necessary to restrain terminal differentiation, whereas the negative regulatory domain was critical for cell survival. Conversely, Myb overexpression enhanced CD8+ T-cell memory formation, polyfunctionality, and recall responses promoting curative antitumor immunity. These findings identify Myb as a pivotal regulator of CD8+ T-cell stemness and highlight the therapeutic potential of increasing Myb activity in CD8+ T cells.

2018-11-01 | GSE112049 | GEO

Expression Profiling of Erythroid Progenitors After MYB shRNA Knockdown

2011-01-03 | GSE25678 | GEO

Expression Profiling of Erythroid Progenitors After MYB shRNA Knockdown

Project description:MYB plays a critical role as a regulator of erythropoieisis. We have shown that MYB silences epsilon and gamma-globin expression in erythroid progenitors. We here examine erythroid cells at the basophilic erythroblast stage of differentiation with MYB shRNA or control lentiviral transduction prior to differentiation. We have cultured CD34 cells and transduced the cells with lentiviruses harboring shRNAs targeting MYB or controls and then allowed the cells to differentiate down the erythroid lineage. At the basophilic erythroblast stage of differentiation, the cells were harvested and total RNA was extracted. This was used to hybridize to Affymetrix expression arrays using the HG-U133 Plus 2.0 platform to ascertain expression differences that occur with the knockdown of MYB.

2011-01-03 | E-GEOD-25678 | biostudies-arrayexpress

MAZ induces MYB expression during the exit from quiescence via the E2F site in the MYB promoter

Project description:Most E2F-binding sites repress transcription through the recruitment of Retinoblasoma (RB) family members until the end of the G1 cell-cycle phase. Although the MYB promoter contains an E2F-binding site, its transcription is activated shortly after the exit from quiescence, before RB family members inactivation, by unknown mechanisms. We had previously uncovered a nuclear factor distinct from E2F, Myb-sp, whose DNA-binding site overlapped the E2F element and had hypothesized that this factor might overcome the transcriptional repression of MYB by E2F-RB family members. We have purified Myb-sp and discovered that Myc-associated zinc finger proteins (MAZ) are major components. We show that various MAZ isoforms are present in Myb-sp and activate transcription via the MYB-E2F element. Moreover, while forced RB or p130 expression repressed the activity of a luciferase reporter driven by the MYB-E2F element, co-expression of MAZ proteins not only reverted repression, but also activated transcription. Finally, we show that MAZ binds the MYB promoter in vivo, that its binding site is critical for MYB transactivation, and that MAZ knockdown inhibits MYB expression during the exit from quiescence. Together, these data indicate that MAZ is essential to bypass MYB promoter repression by RB family members and to induce MYB expression.

2017-10-04 | PXD006857 | Pride

Distal regulation of c-myb expression in human myeloid leukemia cells

Project description:The transcription factor c-Myb a key regulator in proliferation and differentiation of hematopoietic progenitor cells, is precisely regulated during essential cellular processes. Overexpression and rearrangement of c-myb has been reported in human tumors including myeloid leukemia, but exact regulatory mechanisms have remained elusive. Here, we identified, using 4C assay with the c-myb promoter as an anchor, the interaction site at -34k region upstream of c-myb gene that are involved in c-myb expression. Furthermore, we found that the long-range interactions changed with c-myb being down-regulated on differentiation progress in human myeloid leukemia cell lines. Taken together, our date revealed that a potential c-myb enhancer-promoter interactions may be a particularly important regulatory mechanism for c-myb gene expression in human myeloid leukemia cells.

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MicroRNA-15/16 Antagonizes c-Myb to Control Natural Killer Cell Maturation (c-Myb overexpression)

Project description:NK cells develop in the bone marrow and complete their maturation in peripheral organs, but the molecular events controlling maturation are incompletely understood. Utilizing an NK cell-specific miR-15/16 deficient genetic model (15aKO), we identified a critical role for miR-15/16 family microRNAs in the normal maturation of NK cells in vivo, with a specific reduction in mature CD11b+CD27- NK cells in multiple tissues. The mechanism responsible was a block in differentiation, since accelerated NK cell death was not evident, and earlier intermediates of NK cell maturation were expanded. Further, we identified Myb as a direct target of miR-15/16 in NK cells, with Myb expression increased in immature 15aKO NK cells. Following adoptive transfer, immature 15aKO NK cells exhibited defective maturation, which was rescued by ectopic miR-15/16 expression or Myb knockdown. Moreover, Myb overexpression resulted in defective NK cell maturation. Thus, miR-15/16 regulation of Myb controls the normal NK cell maturation program. KY-1 and KY-2 cell lines overexpressing c-Myb

2015-09-03 | E-GEOD-58268 | biostudies-arrayexpress

Definition of aberrant MYB CBP/P300 complex in AML

Project description:Dysregulated gene expression is one of the most prevalent features in human cancers. Here, we show that most subtypes of acute myeloid leukemia (AML) depend on the aberrant assembly of the MYB transcriptional co-activator complex. By rapid and selective peptidomimetic interference with the binding of CBP/P300 to MYB, but not CREB or MLL1, we find that the leukemic functions of MYB are mediated by CBP/P300-mediated co-activation of a distinct set of transcriptional factor complexes that are aberrantly assembled with MYB in AML cells. This therapeutic remodeling is accompanied by dynamic redistribution of CBP/P300 complexes to genes that control cellular differentiation and growth. Thus, aberrantly organized transcription factor complexes control convergent gene expression programs in AML cells. These findings establish a compelling strategy for pharmacologic reprogramming of oncogenic gene expression that supports its targeting for leukemias and other human cancers caused by dysregulated gene control.

2020-12-17 | PXD019708 | Pride

Treg cells from human blood differentiate into non-lymphoid tissue-resident effector cells upon TNFR2 costimulation

Project description:Regulatory T (Treg) cells can facilitate transplant tolerance and attenuate autoimmune- and inflammatory diseases. Therefore, it is clinically relevant to stimulate Treg cell expansion and function in vivo and to create therapeutic Treg cell products in vitro. We report that TNF receptor 2 (TNFR2) is a unique costimulus for naïve, thymus-derived (t)Treg cells from human blood that promotes their differentiation into non-lymphoid tissue (NLT)-resident effector Treg cells, without Th-like polarization. In contrast, CD28 costimulation maintains a lymphoid tissue (LT)-resident Treg cell phenotype. We base this conclusion on transcriptome and proteome analysis of TNFR2- and CD28-costimulated CD4+ Treg cells and conventional T (Tconv) cells, followed by bioinformatic comparison with published transcriptomic Treg cell signatures from NLT and LT in health and disease, including autoimmunity and cancer. These analyses illuminate that TNFR2 costimulation promotes Treg cell capacity for survival, migration, immunosuppression and tissue regeneration. Functional studies confirmed improved migratory ability of TNFR2-costimulated tTreg cells. Flow cytometry validated the presence of the TNFR2-driven Treg cell signature in effector/memory Treg cells from the human placenta as opposed to blood. Thus, TNFR2 can be exploited as driver of NLT-resident Treg cell differentiation for adoptive cell therapy or antibody-based immunomodulation in human disease.

2024-01-24 | PXD048248 | Pride

MYB silencing in CD14-myeloblasts

Project description:The c-Myb transcription factor is highly expressed in immature hematopoietic cells and down-regulated during differentiation. To define the role of c-Myb during the terminal differentiation of hematopoietic precursors, we studied the effects of its silencing in human primary CD14-myeloblasts, which maintain a granulo-monocyte differentiation bipotentiality. c-Myb-silenced myeloblasts were blocked in the G1 phase of the cell cycle at 24 hours post-nucleofection and subsequently were forced towards macrophage differentiation, as demonstrated by immunophenotypic and morphological analysis. Indeed, c-Myb-silenced CD14- cells differentiate to macrophage even after the treatment with ATRA 10-6 M, demonstrating that the c-Myb knockdown strongly impairs the ability of myeloblasts to differentiate to granulocytes. Gene expression profiling of c-Myb-silenced CD14- cells identified some potential c-Myb targets that can account for these effects.

2010-07-14 | GSE21943 | GEO

MicroRNA-15/16 Antagonizes c-Myb to Control Natural Killer Cell Maturation (c-Myb overexpression)

2015-09-03 | GSE58268 | GEO

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