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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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RNA-sequencing of DYRK1A-deficient (CKO) pre-B and pre-T cells

ABSTRACT: Pre-B and pre-T lymphocytes must orchestrate a transition from a highly proliferative state to a quiescent one during development. Cyclin D3 is essential for these cells’ proliferation, but little is known about its post-translational regulation at this stage. Here, we show that the dual specificity tyrosine-regulated kinase 1A (DYRK1A) restrains Cyclin D3 protein levels by phosphorylating T283 to induce its degradation. Loss of DYRK1A activity, via genetic inactivation or pharmacologic inhibition, caused accumulation of Cyclin D3 protein, incomplete repression of E2F-mediated gene transcription, and failure to properly couple cell cycle exit with differentiation. Expression of a non-phosphorylatable Cyclin D3 T283A mutant recapitulated these defects, while inhibition of Cyclin D:CDK4/6 mitigated the effects of DYRK1A inhibition. These data uncover a previously unknown role for DYRK1A in lymphopoiesis, and demonstrate how Cyclin D3 protein stability is negatively regulated during exit from the proliferative phases of B and T cell development. 5 cell populations were analyzed (small pre-B cells, large pre-B cells, quiescent CD4+CD8+ thymocytes, cycling CD4+CD+ thymocytes, and mature granulocytes) from 2 Control mice (pooled) and 2 DYRK1A-deficient mice (pooled) for a total of 10 samples.

ORGANISM(S): Mus musculus

SUBMITTER: John Crispino

PROVIDER: E-GEOD-67052 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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RNA-sequencing of DYRK1A-deficient (CKO) pre-B and pre-T cells

Project description:Pre-B and pre-T lymphocytes must orchestrate a transition from a highly proliferative state to a quiescent one during development. Cyclin D3 is essential for these cells’ proliferation, but little is known about its post-translational regulation at this stage. Here, we show that the dual specificity tyrosine-regulated kinase 1A (DYRK1A) restrains Cyclin D3 protein levels by phosphorylating T283 to induce its degradation. Loss of DYRK1A activity, via genetic inactivation or pharmacologic inhibition, caused accumulation of Cyclin D3 protein, incomplete repression of E2F-mediated gene transcription, and failure to properly couple cell cycle exit with differentiation. Expression of a non-phosphorylatable Cyclin D3 T283A mutant recapitulated these defects, while inhibition of Cyclin D:CDK4/6 mitigated the effects of DYRK1A inhibition. These data uncover a previously unknown role for DYRK1A in lymphopoiesis, and demonstrate how Cyclin D3 protein stability is negatively regulated during exit from the proliferative phases of B and T cell development.

2015-05-01 | GSE67052 | GEO

Expression data from vehicle or PD-0332991 treated human T-ALL lines

2012-12-13 | GSE40635 | GEO

Regulated Capture of Vk Gene Topologically Associating Domains by Transcription Factories

Project description:Antigen receptor gene recombination requires stochastic, monoallelic choice of a single variable gene in each lymphocyte progenitor. However, how this occurs remains unknown. Herein, we report that prior to Vκ to Jκ gene recombination, Igκ alleles reside within spatially different nuclear niches defined by elongating RNA Polymerase II (e-Pol II) and cyclin D3 complexes assembled on the nuclear matrix. Upon cell cycle exit, and cyclin D3 downregulation, only the Vκ allele in the more constrained e-Pol II niche was transcribed. Chromatin modeling and single cell RNA-seq revealed that the nuclear niche favored Vκ flanking CTCF sites, thus shaping the transcribed repertoire. Furthermore, multiple contiguous Vκs oriented away from CTCF sites were preferentially transcribed. Cyclin D3 also repressed monoallelic protocadherin and olfactory genes. These studies of Igκ reveal a general mechanism by which regulated, stochastic chromatin loop capture by fixed e-Pol II complexes generates diversity and couples cell cycle exit to monogenic choice.

2018-08-08 | GSE84705 | GEO

Expression data from vehicle or PD-0332991 treated human T-ALL lines

Project description:Cyclin D3 is critical hematopoiesis and loss of cyclin D3 leads to resistance to transformation of bone marrow progenitors by Notch1-IC. We used a small molecule targeting cyclin D3:CDK4/6 activity to study whether its inhibition is an effective therapeutic strategy. We analyzed T-ALL lines in vitro with PD-0332991 or vehicle control to determine genes affected by the drug. CEM, Jurkat, DND41, and CUTL-1 cell lines were treated with 1 uM PD-0332991 or DMSO for 15 hours prior to RNA extraction and hybridization to Human Genome U133 Plus 2.0 Affymetrix arrays.

2012-12-13 | E-GEOD-40635 | biostudies-arrayexpress

Cell quiescence and reprogramming are distinctive features of pre-leukemic stem cells [H2Bgfp]

Project description:The leukemic stem cell concept is well established in B-acute lymphoblastic leukemia (B-ALL). However, the question of how a primary oncogene reprograms stem cell-like properties in committed B-cells and leads to a pre-neoplastic population remains unclear. Here, we used the PAX5-ELN oncogenic model to demonstrate a causal link between the differentiation blockade, the self-renewal and the emergence of pre-leukemic stem cells (pre-LSCs). Through multi-parametric immunophenotyping, we show that PAX5-ELN oncoprotein disrupts the differentiation of pre-leukemic cells by enforcing the IL7r/JAK-STAT signaling pathway. This disruption is associated with the induction of rare and quiescent pre-LSCs that sustain the leukemia-initiating activity, as assessed using the H2B-GFP model. Integration of transcriptomic and chromatin accessibility data reveals that those quiescent pre-LSCs lose B-cell identity and reactivate an immature molecular program, reminiscent of human B-ALL chemo-resistant cells. Collectively, our study sheds new lights on the biological mechanisms underlying the cell-of-origin of leukemia. We performed gene expression profiling analysis using data obtained from RNA-seq of quiescent or proliferative B-cells PEtg mice.

2023-11-01 | GSE210925 | GEO

Cell quiescence and reprogramming are distinctive features of pre-leukemic stem cells [RNA-seq CTV]

2023-11-01 | GSE210924 | GEO

Global Phosphoproteomics of DYRK1A Inhibition in Glioblastoma Cells

Project description:Here we performed a detailed investigation to delineate the role of DYRK1A in glioblastoma, using both pharmacological and genetic tools combined with global phosphoproteomics. Our data show that DYRK1A inhibitors affect a much broader proportion of the phosphoproteome than DYRK1A knockdown. By overlaying these datasets we identify a pool of 61 putative novel DYRK1A targets, and validate CDC23 Ser588 as a bona-fide DYRK1A substrate. CDC23 is a ubiquitin ligase that degrades mitotic proteins, and DYRK1A inhibiton thereby leads to the accumulation of cyclin B and activation of CDK1.

2021-04-22 | PXD020441 | Pride

A fatty acid oxidation-dependent metabolic shift regulates adult neural stem cell quiescence

Project description:Adult hippocampal neurogenesis is important for certain forms of cognition and failing neurogenesis has been implicated in neuropsychiatric diseases. The neurogenic capacity of hippocampal neural stem/progenitor cells (NSPCs) depends on a balance between quiescent and proliferative states. However, how this balance is regulated remains poorly understood. Here we show that the rate of fatty acid oxidation (FAO) defines quiescence vs. proliferation in NSPCs. Quiescent NSPCs show high levels of carnitine palmitoyltransferase 1a (Cpt1a)-dependent FAO, which is downregulated in proliferating NSPCs. Pharmacological inhibition and conditional deletion of Cpt1a in vitro and in vivo leads to altered NSPC behavior, showing that Cpt1a-dependent FAO is required for stem cell maintenance and proper neurogenesis. Strikingly, experimental manipulation of malonyl-CoA, the metabolite that regulates levels of FAO, is sufficient to induce exit from quiescence and to enhance NSPC proliferation. Thus, the data presented here identify a shift in FAO metabolism that governs NSPC behavior and suggest an instructive role for fatty acid metabolism in regulating NSPC activity.

2019-11-15 | PXD005598 | Pride

Transcriptional profiling analysis of pre-selected DP thymocytes in response to positive and negative selection signals

Project description:Sustained Ca2+ entry into CD4+CD8+ double-positive thymocytes is required for positive selection. We identified a voltage-gated Na+ channel (VGSC), essential for positive selection of CD4+ T cells. Pharmacological inhibition of VGSC activity inhibited sustained Ca2+ influx induced by positive-selecting ligands and in vitro positive selection of CD4+ but not CD8+ T cells. In vivo shRNA knockdown of Scn5a specifically inhibited positive selection of CD4+ T cells. Ectopic expression of VGSC in peripheral AND CD4+ T cells bestowed the ability to respond to a positively selecting ligand, directly demonstrating VGSC expression was responsible for increased sensitivity. Thus active VGSCs in thymocytes provides a mechanism by which a weak positive selecting signal can induce sustained Ca2+ signals required for CD4+ T cell development. Pre-selected AND DP thymocytes were stimulated with plate bound peptide-loaded I-Ek Ig dimers. Genes were differentially regulated by positive and negative selection signals. The goal of this study is to identify ion-channel related genes critical for thymic positive selection, given the sustained Ca2+ entry into double positive thymocytes is required for positive selection. Total RNA of pre-selected AND thymocytes stimulated with I-Ek Ig dimers loaded with the positively-selecting peptide gp250, the negatively-selecting agonist peptide MCC, or the non-selecting control peptide Hb were used for the transcriptional profiling analysis. We found 28 genes were differentially down-regulated by MCC stimulation but upregulated by gp250 stimulation. One of them, scn4b, was ion-channel related.

2012-06-30 | E-GEOD-38909 | biostudies-arrayexpress

Synergistic roles of DYRK1A and GATA1 in trisomy 21 megakaryopoiesis

Project description:Patients with Down syndrome (DS, trisomy 21, T21) are at increased risk of transient abnormal myelopoiesis (TAM) and acute megakaryoblastic leukemia (ML-DS). Both TAM and ML-DS require prenatal somatic mutations in GATA1, resulting in the truncated isoform GATA1s. The mechanism by which individual chromosome 21 (HSA21) genes synergize with GATA1s for leukemic transformation is challenging to study, in part due to limited human cell models with wild type GATA1 or GATA1s. HSA21-encoded DYRK1A is overexpressed in ML-DS and may be a therapeutic target. To determine how DYRK1A influences hematopoiesis in concert with GATA1s, we used gene editing to disrupt all 3 alleles of DYRK1A in isogenic T21 induced pluripotent stem cells (iPSCs) with and without the GATA1s mutation. Unexpectedly, hematopoietic differentiation revealed that DYRK1A loss combined with GATA1s leads to increased megakaryocyte proliferation and decreased maturation. This proliferative phenotype was associated with upregulation of D-type cyclins and hyperphosphorylation of Rb to allow E2F release and de-repression of its downstream targets. Notably, DYRK1A loss had no effect in T21/wtGATA1 megakaryocytes. These surprising results suggest that increased DYRK1A expression may be protective against TAM and ML-DS and that DYRK1A inhibition would not be a therapeutic option for GATA1s-associated leukemias.

2023-11-04 | GSE243702 | GEO

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