RNA-seq of granulocytes derived from control and AK2 depleted human HSPCs
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE179320 | GEO | 2021/07/06
REPOSITORIES: GEO
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Project description:Reticular Dysgenesis (RD) is a rare but devastating form of severe combined immunodeficiency, characterized by a maturation arrest of the myeloid and lymphoid lineages paired with sensorineural hearing loss. RD is caused by biallelic loss-of-function mutations in the mitochondrial enzyme adenylate kinase 2 (AK2). Understanding the gene expression impact of AK2 loss-of-function on a single cell level would not only allow us to develop rational therapies for RD and other mitochondrial diseases but enable us to reconstruct metabolic changes that occur during development and how they impact cell fate decisions.
2021-07-06 | GSE179346 | GEO
Project description:Reticular dysgenesis (RD) is a human Severe Combined Immunodeficiency mainly characterized by a profound neutropenia and lymphopenia. This pathology is due to mutations in the adenylate kinase 2 (AK2) gene, resulting in the loss of AK2 protein expression. AK2 is a mitochondrial protein, which regulates the homeostasis of cellular adenine nucleotides by converting ADP into ATP and AMP. Using a RNA interference strategy, we dissected the role of AK2 during the commitment of hematopoietic progenitors towards the lymphoid or myeloid lineage. Our results demonstrated that AK2 knock-down progenitors have reduced proliferative and survival capacity and differentiation toward the lymphoid or granulocytic lineage is abrogated. In this report, we also highlighted that AK2 signaling pathway is essential to control energy production and to maintain the integrity of all mitochondrial functions. This steady state may be disturbed in RD patients leading to a blockade of the differentiation process.
2015-06-21 | E-MTAB-2680 | biostudies-arrayexpress
Project description:Recent studies have linked bioenergetic regulation to cellular differentiation. However, the contribution of metabolic communication among subcellular components to the fate of progenitor cells remains unclear. Adenylate kinase 2 (AK2) is an adenylate phosphotransferase localized in the mitochondrial intermembrane space. Although AK2 mutations in human can cause a severe combined immunodeficiency with neutropenia, named reticular dysgenesis (RD), underlying mechanisms have not yet been elucidated. To address these questions, we established induced pluripotent stem cells (iPSCs) from two RD patients. Metabolic flux analysis revealed that AK2 mediates the distribution of glycolytic metabolites into the tricarbon acid cycle in mitochondria. Hematopoietic differentiation from RD-iPSCs was profoundly impaired. Intriguingly, RD-iPSC-derived hematopoietic progenitors exhibited an immature mitochondrial morphology, discordant ATP distribution among the mitochondria and nucleus, and alteration of global transcriptional profiles. These results highlight the importance of stage-specific intracellular energy communication for controlling the fate of multipotential progenitors.
2018-09-03 | GSE76761 | GEO
Project description:Adenylate kinase 2 (AK2) is a wide-spread and highly conserved protein kinase whose main function is to catalyze the exchange of nucleotide phosphate groups. In this study, we showed that AK2 regulated tumor cell metastasis in lung adenocarcinoma. Positive expression of AK2 is related to lung adenocarcinoma progression and poor survival of patients. Knockdown or knockout of AK2 inhibited, while overexpression of AK2 promoted, human lung adenocarcinoma cell migration and invasion ability. Differential proteomics results showed that AK2 might be closely related to epithelial-mesenchymal transition (EMT). Further research indicated that AK2 regulated EMT occurrence through the Smad-dependent classical signaling pathways as measured by western blot and qPCR assays. Additionally, in vivo experiments showed that AK2-knockout in human lung tumor cells reduced their EMT-like features and formed fewer metastatic nodules both in liver and in lung tissues. In conclusion, we uncover a cancer metastasis-promoting role for AK2 and provide a rationale for targeting AK2 as a potential therapeutic approach for lung cancer.
2021-09-18 | PXD028247 | Pride
Project description:RNA-seq of granulocytes derived from control and AK2 depleted human HSPCs
| PRJNA743237 | ENA
Project description:Adenylate kinase 2 (AK2) is a wide-spread and highly conserved protein kinase whose main function is to catalyze the exchange of nucleotide phosphate groups. In this study, we showed that AK2 regulated tumor cell metastasis in lung adenocarcinoma. Positive expression of AK2 is related to lung adenocarcinoma progression and poor survival of patients. Knockdown or knockout of AK2 inhibited, while overexpression of AK2 promoted, human lung adenocarcinoma cell migration and invasion ability. Differential proteomics results showed that AK2 might be closely related to epithelial-mesenchymal transition (EMT). Further research indicated that AK2 regulated EMT occurrence through the Smad-dependent classical signaling pathways as measured by western blot and qPCR assays. Additionally, in vivo experiments showed that AK2-knockout in human lung tumor cells reduced their EMT-like features and formed fewer metastatic nodules both in liver and in lung tissues. In conclusion, we uncover a cancer metastasis-promoting role for AK2 and provide a rationale for targeting AK2 as a potential therapeutic approach for lung cancer.
2021-09-09 | PXD028231 | iProX
Project description:Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA binding protein that regulates a diverse array of biological processes, including recycling small nuclear ribonucleic acids (snRNAs) back to the spliceosome. Here we describe nine individuals from six independent families with a multisystem disorder, characterised by intellectual disability, developmental delay, brain anomalies and 46, XY-specific gonadal dysgenesis, who harbour recessive variants in the SART3 gene. Knockdown of the fly orthologue of SART3, Rnp4f, demonstrates a conserved role in neuronal and testicular development. Human induced pluripotent stem cells (iPSCs) carrying patient SART3 variants have disrupted neuronal and gonadal differentiation in vitro. These iPSCs have significant disruption to multiple signalling pathways and complexes, including spliceosome components and mRNA splicing. We propose that biallelic variants in the SART3 gene underlie a novel spliceosomopathy characterised by neuronal defects and testicular dysgenesis.
2023-06-11 | PXD032816 | Pride
Project description:ZNF384-rearranged fusion oncoproteins (FO) define a subset of lineage ambiguous leukemias, but the mechanistic role of ZNF384 FO in leukemogenesis and lineage ambiguity is poorly understood. Here, using viral expression in mouse and human hematopoietic stem and progenitor cells (HSPCs) and a Ep300-Zfp384 mouse model we show that ZNF384 FO promote hematopoietic expansion, myeloid lineage skewing, and self-renewal. In mouse HSPCs, concomitant lesions such as NRASG12D, were required for fully penetrant leukemia, whereas expression of ZNF384 FO drove development of B/myeloid leukemia in human HSPCs, with sensitivity of human ZNF384r leukemia to FLT3 inhibition in vivo. Mechanistically, ZNF384 FO occupy a subset of predominantly intragenic/enhancer regions with increased histone 3 lysine acetylation suggesting enhancer function. These data define a paradigm for FO-driven lineage ambiguous leukemia, in which expression in HSPCs results in deregulation of lineage-specific genes and hematopoietic skewing, progressing to full leukemic transformation in the presence of proliferative stress.
2022-03-16 | PXD028481 | Pride
Project description:Severe congenital neutropenia (CN) is a pre-leukemia syndrome that, in the majority of patients, is caused by heterogeneous ELANE mutations encoding neutrophil elastase (NE). To study leukemogenesis associated with CN we generated CN and CN/AML patient-specific induced pluripotent stem cells (iPSCs). Additional mutations in leukemia-relevant genes, CSF3R and RUNX1, were introduced using CRISPR/Cas9 gene-editing. Consequently, we performed in vitro embryoid body (EB)-based hematopoietic and myeloid differentiation of generated iPSC lines. On day 14-17 of EB-based differentiation, iPSC-derived CD45+CD34+ cells were harvested and mRNA was isolated using RNeasy Mini- or Micro Kit (Qiagen). Sequencing libraries were prepared using the TruSeq RNA Sample Prep Kit (Illumina). Poly (A) selected single-read and pair-read sequencing libraries were sequenced on the Illumina platform in order to compare the transcriptomes of CN and CN/AML iPSCs-derived HSPCs from 2 CN/AML patients. Next, we identified that BAALC knockout resulted in a dramatic induction of granulocytic differentiation and a significant reduction in proliferation of CN/AML iPSC-derived HSPCs. To identify BAALC-dependent leukemia-associated gene expression, we compared the transcriptomes of CN/AML iPSCs before and after BAALC KO using a similar approach described above for CN and CN/AML iPSCs-derived HSPCs.
2021-03-08 | E-MTAB-10162 | biostudies-arrayexpress
Project description:Emergency myelopoiesis (EM) is critical for immune defense against pathogens, which requires rapid replenishing of mature myeloid cells. The EM process involves a rapid cell cycle switch from the quiescent hematopoietic stem cells (HSCs) to highly proliferative myeloid progenitors (MPs). How this cell cycle switch is regulated remains poorly understood. Here, we reveal that ATG7, a critical autophagy factor is essential for the rapid proliferation of MPs during human myelopoiesis. Peripheral blood (PB) mobilized HSPCs with ATG7 knock-down or HSPCs derived from ATG7-/- human embryonic stem cells (hESCs) exhibit severe defect in proliferation at MP stage during myeloid/granulocytes differentiation. ATG7 deficient MPs show substantially elevated P53 protein and up-regulation of P53 signaling pathway genes. Mechanistically, ATG7 dependent autophagy mediates P53 degradation in lysosome that allows normal proliferation of MPs. Together, we reveal an essential role of autophagy for P53 degradation in cell cycle switch during human myelopoiesis
2023-01-25 | GSE223219 | GEO