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Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation

ABSTRACT: SET domain containing 2 (Setd2), encoding a histone methyltransferase, is associated with many hematopoietic diseases when mutated. By generating a novel exon 6 conditional knockout mouse model, we described an essential role of Setd2 in maintaining the adult hematopoietic stem cells. Loss of Setd2 results in leukopenia, anemia, and increased platelet accompanied with hypocellularity, erythroid dysplasia, and mild fibrosis in bone marrow. Setd2 knockout mice show significantly decreased hematopoietic stem and progenitor cells except for erythroid progenitors. Setd2 knockout hematopoietic stem cells fail to establish long-term bone marrow reconstitution after transplantation, because of the loss of quiescence, increased apoptosis, and reduced multiple-lineage terminal differentiation potential. Bioinformatic analysis revealed that the hematopoietic stem cells exit of quiescence and commit to differentiation, which lead to hematopoietic stem cells exhaustion. Mechanistically, we attribute an important Setd2 function in murine adult hematopoietic stem cells to the inhibition of the Nsd1/2/3 transcriptional complex, which recruits super elongation complex and controls RNA polymerase II elongation on a subset of target genes including Myc. Our results reveal a critical role of Setd2 in regulating quiescence and differentiation of HSCs through restricting the NSDs/SEC mediated RNA Polymerase II elongation.

ORGANISM(S): Mus musculus

PROVIDER: GSE112550 | GEO | 2018/05/01

REPOSITORIES: GEO

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Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation

Project description:Setd2 regulates quiescence and differentiation of adult hematopoietic stem cells by restricting RNA polymerase II elongation

| PRJNA448165 | ENA

FoxM1 is essential for quiescence and maintenance of hematopoietic stem cell

Project description:FoxM1, a mammalian Forkhead Box M1 protein, is known as a typical proliferation-associated transcription factor that regulates of G1/S and G2/M transition in the proliferating cells. However, the in vivo function of FoxM1 in adult stem cells remains unknown. Here, we found that FoxM1 is highly expressed in hematopoietic stem cells (HSCs) and is essential for maintaining quiescence and self-renewal of HSCs in vivo. FoxM1-deficient mice developed leukopenia, thrombocytopenia and neutropenia with an approximately 6-fold decrease in HSC pool size, which is associated with a failure of G0 cell cycle regulation and increased cell cycling in HSCs. FoxM1 absence did not affect lineage commitment of HSCs and progenitors. However, FoxM1 loss significantly reduced the repopulating capacity and self-renewal of long-term HSC in a cell-autonomous manner. Mechanistically, FoxM1 loss markedly down-regulates the expression of orphan nuclear receptor Nurr1, known to regulate HSC quiescence. We found that FoxM1 directly bound the promoter region of Nurr1 and induced transcriptional activity of Nurr1 promoter in vitro, and forced expression of Nurr1 rescued FoxM1-deletion-induced G0 loss of HSC-enriched population in vitro. Thus, our studies show a previously unrecognized role of FoxM1 as a critical regulator of HSC quiescence and self-renewal by controlling Nurr1-mediated pathways. The Hematopoietic Stem Cells (HSCs) were sorted from FoxM1[fl/fl] and Tie2-Cre FoxM1[fl/fl] mice, then amplified with Ovation Pico WTA System V2 before microarray analysis. There are 3 samples from FoxM1[fl/fl]mice and 3 samples from Tie2-Cre FoxM1[fl/fl] mice.

2015-06-15 | E-GEOD-62360 | biostudies-arrayexpress

Setd2 deficiency impaired erythroid differentiation and accelerated Myelodysplastic Syndrome(MDS) - associated leukemogenesis through S100A8 and S100A9

Project description:Setd2, the histone H3 lysine 36 methyltransferase, plays an important role in the pathogenesis of hematologic malignancies. The research on the role of Setd2 in leukemogenesis has made great progress, but its role in MDS is still unknown. Here, we knock out Setd2 in the NUP98-HOXD13 transgenic (NHD13 Tg) mouse, and demonstrate that loss of Setd2 accelerates the transformation of MDS into AML. The conditional deletion of Setd2 also interferes the differentiation of hematopoietic stem and progenitor cells (HSPCs), and results in the decrease of granulocyte monocyte progenitor (GMP) cells, increase of megakaryocyte erythroid progenitor (MEP) cells and common myeloid progenitor (CMP) cells. Loss of Setd2 impairs erythroid differentiation, includes cell cycle arrest in G2-M and enhances the selt-renewal ability of HSPCS. Our RNA-seq,ChIP-seq and WGBS analysis indicats that S100A8 and S100A9 are direct target genes of H3K36me3 and expression of heterodimeric S100 calcium-binding proteins S100A8 and S100A9 are downregulated in HSPCs when Setd2 deficiency. Addition of recombinant S100A8 or S100A9 weakens the clonogenic progenitors of Setd2 deficient HSPCs. Therefore, our results demonstrate that loss of Setd2 promotes the transformation of MDS into AML, which proves Setd2 as a tumor suppressor in MDS, and provides a potential therapeutic target for MDS associated leukemia.

2020-07-02 | GSE129691 | GEO

FBXO9 in Murine Inversion 16 AML

Project description:The hematopoietic system is maintained throughout life by hematopoietic stem cells that are capable of differentiation to all hematopoietic lineages. An intimate balance between self-renewal, differentiation, and quiescence is required to maintain hematopoiesis. Disruption of this balance can result in hematopoietic malignancy, including acute myeloid leukemia (AML). FBXO9, from the F-box ubiquitin E3 ligases, is down-regulated in patients with AML compared to normal bone marrow. FBXO9 is a substrate recognition component of the Skp1-Cullin-F-box (SCF)-type E3 ligase complex. FBXO9 is highly expressed in hematopoietic stem and progenitor populations, which contain the tumor-initiating population in AML. In AML patients, decrease in FBXO9 expression is most pronounced in patients with the inversion of chromosome 16 (Inv(16)), a rearrangement that generates the transcription factor fusion gene, CBFB-MYH11. To study FBXO9 in malignant hematopoiesis, we generated a conditional knockout mouse model using a novel CRISPR/Cas9 strategy. Our data shows that deletion of Fbxo9 in mice expressing Cbfb-MYH11 leads to markedly accelerated and aggressive leukemia development. In addition, we find loss of FBXO9 leads to increased proteasome expression and tumors are more sensitive to bortezomib suggesting that FBXO9 expression may predict patient response to bortezomib treatment.

2019-11-27 | PXD014387 | Pride

Effect of aryl hydrocarbon receptor (Ahr) gene knockout on expression profiles of murine hematopoietic stem cells

Project description:As part of a study of the role of the aryl hydrocarbon receptor (Ahr) in maintenance and senescence of hematopoietic stem cells (HSC), global gene expression profiling was done with HSC isolated from Ahr-knockout and wild-type mice. HSC from young-adult (8 wk old) AhR-KO mice had changes in expression of many genes related to HSC maintenance, consistent with the phenotype observed in aging Ahr-KO mice: decreased survival rate, splenomegaly, increased circulating white blood cells, hematopoietic cell accumulation in tissues, anemia, increased numbers of stem/progenitor and lineage-committed cells in bone marrow, decreased erythroid progenitor cells in bone marrow, and decreased self-renewal capacity of HSC. 7 samples: 3 Ahr knockout, 4 wild-type

2013-11-08 | E-GEOD-46976 | biostudies-arrayexpress

Effect of aryl hydrocarbon receptor (Ahr) gene knockout on expression profiles of aged (18-month-old) murine hematopoietic stem cells

Project description:As part of a study of the role of the aryl hydrocarbon receptor (Ahr) in maintenance and senescence of hematopoietic stem cells (HSC), global gene expression profiling was done with HSC isolated from 18-month-old Ahr-knockout and wild-type mice. HSC from aged AhR-KO mice had changes in expression of many genes related to HSC maintenance, consistent with the phenotype observed in aging Ahr-KO mice: decreased survival rate, splenomegaly, increased circulating white blood cells, hematopoietic cell accumulation in tissues, anemia, increased numbers of stem/progenitor and lineage-committed cells in bone marrow, decreased erythroid progenitor cells in bone marrow, and decreased self-renewal capacity of HSC. 10 samples: 5 Ahr knockout, 5 wild-type

2015-03-28 | E-GEOD-67378 | biostudies-arrayexpress

FoxM1 is essential for quiescence and maintenance of hematopoietic stem cell

2015-06-15 | GSE62360 | GEO

Role of the histone demethylase KDM2B in hematopoietic homeostasis and malignancies [RNA-seq]

Project description:Development of the hematopoietic system is dynamically controlled by the interplay of transcriptional and epigenetic networks to determine cellular identity. Those networks are critical for homeostasis and frequently dysregulated in leukemias. We identified histone demethylase Kdm2b as a critical regulator of definitive hematopoiesis and lineage specification of hematopoietic stem and progenitor cells (HSPCs). RNA sequencing in murine HSPCs and genome-wide chromatin immunoprecipitation studies in human leukemias revealed that Kdm2b regulates differentiation, lineage choice, cytokine signaling, and quiescence. Comparison of gene expression in wild-type and knockout HSPCs

2016-02-22 | E-GEOD-70728 | biostudies-arrayexpress

Induction of S100A8/S100A9 mediates the erythroid differentiation block in ribosomal protein S14 haploinsufficiency

Project description:Schneider RK, Schenone M, Kramann R, Ferreira MV, Joyce CE, Hartigan C, Beier F, Brümmendorf TH, Gehrming U, Platzbecker U, Buesche G, Chen MC, Waters CS, Chen E, Chu LP, Novina CD, Lindsley RC, Carr SA, Ebert BL. Nat Med, 2016. Heterozygous deletion of RPS14 occurs in del(5q) MDS and has been linked to impaired erythropoiesis, characteristic of this disease subtype. We generated a murine model with conditional inactivation of Rps14 and demonstrated a p53-dependent erythroid differentiation defect with apoptosis at the transition from polychromatic to orthochromatic erythroblasts resulting in age-dependent progressive anemia, megakaryocyte dysplasia, and loss of hematopoietic stem cell (HSC) quiescence. Using quantitative proteomics, we identified significantly increased expression of proteins involved in innate immune signaling, particularly the heterodimeric S100A8/S100A9 proteins in purified erythroblasts. S100A8 expression was significantly increased in erythroblasts, monocytes and macrophages and recombinant S100A8 was sufficient to induce an erythroid differentiation defect in wild-type cells. We rescued the erythroid differentiation defect in Rps14 haploinsufficient HSCs by genetic inactivation of S100a8 expression. Our data link Rps14 haploinsufficiency to activation of the innate immune system via induction of S100A8/A9 and the p53-dependant erythroid differentiation defect in del(5q) MDS.

2016-01-26 | MSV000079482 | MassIVE

Comparison of gene expression pattern between Wild-type and Setd2 knockout mESCs [Affymetrix]

Project description:SETD2/HYPB has been known as a histone H3K36 specific methyltransferase. However, its roles in physiology such as development and cellular function remain unclear. In this study, using mESCs as cellular model, we show that Setd2 mainly regulates differentiation of murine embryonic stem cells (mESCs) towards primitive endoderm. This study aimed at exploring how did Setd2 regulate primitive endoderm. differentiation. We used microarrays to detail the global programme of gene expression controled by setd2, which is required for endoderm differentiation. Wild type and Setd2 knockout mESCs were selected for RNA extraction and hybridization on Affymetrix GeneChip® mouse genome 430 2.0 arrays. We sought to obtain some deregulated genes, which were required for primitive endoderm differentiation. For comparison, three biological repeats of each were performed.

2014-10-14 | E-GEOD-54931 | biostudies-arrayexpress

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