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Transcriptional and epigenetic reprogramming mediated by chronic IL1β exposure drives self-renewal ability and myeloid priming in TET2 deficient stem and progenitor cells [Bisulfite-Seq]

ABSTRACT: Clonal hematopoiesis (CH) increases risk for the development of hematological malignancy and cardiovascular disease. IL1β is elevated in patients with CH and its inhibition mitigates cardiovascular risk in murine models with Tet2 loss-of-function. How IL1β alters population dynamics of hematopoietic cells upon Tet2 deletion (Tet2-KO) is not well understood. We demonstrated IL1β expands Tet2-KO neutrophils, monocytes/macrophages, and long-term hematopoietic stem cells with reduced lymphopoiesis. IL1β promotes myeloid bias over other lineages coinciding with failure to demethylate lineage associated enhancer and transcription factor binding sites in Tet2-KO HSPCs. IL1β enhanced self-renewal ability of Tet2-KO HSPCs by upregulating genes associated with self-renewal potential and by failure to demethylate binding sites of transcription factors promoting differentiation. IL1β-mediated premalignant phenotype is reversed by IL1β antagonist anakinra or deletion of the Il1 receptor, in vivo. Our results demonstrated that targeting IL-1 signaling could be an efficient early intervention strategy in preleukemic disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE210025 | GEO | 2023/10/27

REPOSITORIES: GEO

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Transcriptional and epigenetic reprogramming mediated by chronic IL1β exposure drives self-renewal ability and myeloid priming in TET2 deficient stem and progenitor cells [10x_scRNAseq]

Project description:Clonal hematopoiesis (CH) increases risk for the development of hematological malignancy and cardiovascular disease. IL1β is elevated in patients with CH and its inhibition mitigates cardiovascular risk in murine models with Tet2 loss-of-function. How IL1β alters population dynamics of hematopoietic cells upon Tet2 deletion (Tet2-KO) is not well understood. We demonstrated IL1β expands Tet2-KO neutrophils, monocytes/macrophages, and long-term hematopoietic stem cells with reduced lymphopoiesis. IL1β promotes myeloid bias over other lineages coinciding with failure to demethylate lineage associated enhancer and transcription factor binding sites in Tet2-KO HSPCs. IL1β enhanced self-renewal ability of Tet2-KO HSPCs by upregulating genes associated with self-renewal potential and by failure to demethylate binding sites of transcription factors promoting differentiation. IL1β-mediated premalignant phenotype is reversed by IL1β antagonist anakinra or deletion of the Il1 receptor, in vivo. Our results demonstrated that targeting IL-1 signaling could be an efficient early intervention strategy in preleukemic disorders.

2023-10-27 | GSE209994 | GEO

Identify the key signaling pathway involved in the Tet2 deficiency-induced clonal hematopoiesis

Project description:To investigate the signaling pathway required for the Tet2 mutant associated clonal hematopoiesis, we identified the activated signaling pathway in Tet2-deficient hematopoietic stem/progenitor cells compared to WT cells and using transgentic mouse model to validate our findings. In short, the cGAS-STING pathway is activated in Tet2-deficient HSPCs and promotes the development of CH associated with Tet2 deficiency.

2023-05-15 | GSE232384 | GEO

Non-catalytic functions of Tet2 are essential to regulate hematopoietic stem and progenitor cell homeostasis

Project description:To identify genes that are influenced by the catalytic and non-catalytic functions of Tet2 in hematopoietic stem and progenitor cells (HSPCs), we analyzed the gene expression profiles of Tet2 catalytic mutant (Tet2 Mut), Tet2 knockout (Tet2 KO) and wild-type HSPCs (or LSK, Lin–Sca-1+c-Kit+) and multi-potent progenitor (or MPP, Lin–) cells by RNA-seq.

2019-08-05 | GSE132090 | GEO

Tet2 deficiency altered hematopoietic stem and progenitor cells ageing process

Project description:we compared self-renewal and lineage specification of WT and Tet2-deficient HSPCs during ageing and demonstrated that Tet2 ablation alters age-dependent HSC functional decline, revealing a disparate ageing process in the Tet2-deficient haemopoietic system.

2023-08-11 | GSE183675 | GEO

Tet2-mediated epigenetic modifications during aging of hematopoietic stem and progenitor cells

2023-09-10 | GSE157592 | GEO

Aspartyl-tRNA synthetase 2 orchestrates iron-sulfur metabolism in hematopoietic stem cells via fine-tuning alternative RNA splicing

Project description:Aspartyl-tRNA synthetase 2 (Dars2) is involved in the regulation of mitochondrial protein synthesis and tissue-specific mitochondrial unfolded protein response (UPRmt). The role of Dars2 in the self-renewal and differentiation of hematopoietic stem cells (HSCs) is unknown. Here we show that knockout (KO) of Dars2 significantly impairs the maintenance of HSCs and progenitor cells (HSPCs) without involving its tRNA synthetase activity. Dars2 KO results in significantly reduced expression of Srsf2/3/6 and impairs multiple events of mRNA alternative splicing (AS). Dars2 directly localizes to Srsf3 labeled spliceosomes in HSPCs and regulates the stability of Srsf3. Dars2-deficient HSPCs exhibit aberrant AS of mTOR and Slc22a17. Dars2 KO greatly suppresses the levels of labile ferrous iron and iron-sulfur cluster containing proteins, which dampens mitochondrial metabolic activity and DNA damage repair pathway in HSPCs. Our study reveals that Dars2 plays an unprecedented role in the iron-sulfur metabolism and maintenance of HSPCs by modulating RNA splicing.

2023-09-26 | PXD045562 | Pride

p300 suppresses the transition of myelodysplastic syndrome to acute myeloid leukemia [ChIP-seq II]

Project description:The p300 lysine acetyltransferase (KAT) can function as an oncogene or a tumor suppressor in hematologic malignancies. We have identified a tumor suppressor role for p300 in myelodysplastic syndrome (MDS) driven by Tet2 deficiency. Compared to Tet2-null hematopoietic stem and progenitor cells (HSPCs), HSPCs lacking both p300 and Tet2 (double knock out, DKO) displayed enhanced proliferation and impaired differentiation. Consequently, p300Δ/Δ Tet2-/- mice developed acute myeloid leukemia. p300 loss in Tet2-/- HSPCs induced a global epigenomic reprogramming that enhanced leukemogenicity at least in part by increasing expression of Myb, as knock-down of Myb specifically hindered the proliferation of the DKO HSPCs. We show that p300 KAT activity regulates the function of Tet2 null HSPCs, and that augmenting p300 function impairs their unlimited self-renewal. Such a strategy could prove useful in individuals with Tet2 deficient hematopoiesis or MDS.

2021-11-03 | GSE154493 | GEO