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Sca-1 is an early-response target of histone deacetylase inhibitors and marks hematopoietic cells with enhanced function

ABSTRACT: Expression profiles of LSK cells stimulated for 24h in the presence or in the absence of of valproic acid (VPA) The molecular process that underlies the biological effects of valproic acid (VPA), a widely used histone deacetylase inhibitor, on HSPCs was investigated by studying the early-response genes of VPA. Genome-wide gene expression studies revealed overrepresentation of genes involved in glutathione metabolism, receptor and signal transducer activity and changes in the HSPCs surface profile following short, 24h VPA treatment. Sca-1, a well-known and widely used stem cell surface marker, was identified as a prominent VPA target.VPA strongly preserved Sca-1 expression on LSK cells, but also re-activated Sca-1 on committed progenitor cells that were Sca-1 negative, thereby reverting them to the LSK phenotype. We demonstrated that re-acquired Sca-1 expression coincided with induced self-renewal capacity as measured by in vitro re-plating assays, while Sca-1 itself was not required for the biological effects of VPA as demonstrated using Sca-1 deficient progenitor cells. We show that VPA can induce several genes involved in signal transduction of which Sca-1 was shown to mark cells with increased self-renewal capacity.

ORGANISM(S): Mus musculus

PROVIDER: GSE41020 | GEO | 2012/09/25

SECONDARY ACCESSION(S): PRJNA175906

REPOSITORIES: GEO

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Sca-1 is an early-response target of histone deacetylase inhibitors and marks hematopoietic cells with enhanced function

Project description:Expression profiles of LSK cells stimulated for 24h in the presence or in the absence of of valproic acid (VPA) The molecular process that underlies the biological effects of valproic acid (VPA), a widely used histone deacetylase inhibitor, on HSPCs was investigated by studying the early-response genes of VPA. Genome-wide gene expression studies revealed overrepresentation of genes involved in glutathione metabolism, receptor and signal transducer activity and changes in the HSPCs surface profile following short, 24h VPA treatment. Sca-1, a well-known and widely used stem cell surface marker, was identified as a prominent VPA target.VPA strongly preserved Sca-1 expression on LSK cells, but also re-activated Sca-1 on committed progenitor cells that were Sca-1 negative, thereby reverting them to the LSK phenotype. We demonstrated that re-acquired Sca-1 expression coincided with induced self-renewal capacity as measured by in vitro re-plating assays, while Sca-1 itself was not required for the biological effects of VPA as demonstrated using Sca-1 deficient progenitor cells. We show that VPA can induce several genes involved in signal transduction of which Sca-1 was shown to mark cells with increased self-renewal capacity. These data consist of total mRNA obtained from hematopoietic cells cultured for 24h in the presence or absence of valproic acid. All samples were analyzed in independent biological triplicates.

2012-09-25 | E-GEOD-41020 | biostudies-arrayexpress

Expression data from untreated and valproic acid (VPA) treated CD34+ Hematopoietic Stem Cells (HSCs)

Project description:Histone deacetylase (HDAC) inhibitors are widely utilized in hematopoietic malignance therapy; nevertheless, little is currently known concerning their effects on normal myelopoiesis. In order to investigate a putative interference of HDAC inhibitors in myeloid commitment of hematopoietic stem/progenitor cells (HSPCs) we treated CD34+ cells with valproic acid (VPA). Moreover, we investigate changes in gene expression induced by VPA treatment on HSPCs, by means of microarray analysis in VPA treated and untreated (CTR) CD34+ cells. VPA treatment induced H4 histone acetylation in CD34+ cells and blocked them in G0-G1 phase of cell cycle. CD34 expression is maintained for a longer time in VPA treated cells, while the physiological decrease of CD34 antigen occurred in CTR cells. Moreover, VPA favored erythrocyte and megakaryocyte differentiation at the expense of granulocyte and mono-macrophage lineages, as demonstrated by immunophenotyping, morphological and clonogenic analysis. Finally, we demonstrated that VPA up-regulated master gene regulators of erythrocyte and megakaryocyte differentiation (GFI1B and MLLT3) through histone iper-acetylation of their promoters. These results indicate that VPA treatment enhances erythrocyte and megakaryocyte differentiation at the expense of granulocyte and mono-macrophage one. Microarray data provide for the first time a detailed molecular support for the biological effects promoted by VPA treatment in HSPCs. Human CD34+ cells were purified from umbilical Cord Blood (CB) samples. After an initial 24 hours of incubation, CD34+ cells were exposed to VPA. Total cellular RNA was extracted from untreated (CTR) and VPA treated CD34+ HSCs after 48 hours of treatment.

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The combination of valproic acid and lithium prevents hematopoietic stem/progenitor cell differentiation.

Project description:Expression profiles of 7-day cultured HSPCs in the presence or absence of valproic acid and/or lithium. Two small molecules, valproic acid (VPA) and lithium (Li), were tested to inhibit differentiation of hematopoietic stem/progenitor (HSPC) cells in culture. HSPCs exposed to VPA and Li during differentiation-inducing culture preserved an immature cell phenotype, provided radioprotection to lethally irradiated recipients and enhanced in vivo repopulating potential. Furthermore, VPA and Li synergistically preserved expression of stem cell-related genes and repressed genes involved in differentiation. Target genes were collectively co-regulated during normal hematopoietic differentiation. Additionally, transcription factor networks were identified as possible primary regulators. Our results demonstrate that the combination of VPA and Li potently prevents differentiation at the biological and the molecular level, and provide evidence to suggest that combinatorial screening of chemical compounds may uncover possible additive/synergistic effects to modulate stem cell fate decisions. These data consist of total mRNA obtained from hematopoietic cells cultured for 7 days in the presence or absence of valproic acid and/or lithium. All samples were analyzed in independent biological triplicates.

2011-12-15 | E-GEOD-34088 | biostudies-arrayexpress

Expression data from untreated and valproic acid (VPA) treated CD34+ Hematopoietic Stem Cells (HSCs)

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2011-07-12 | E-GEOD-30517 | biostudies-arrayexpress

Differential expression of Hdc-/- VS WT hematopoietic stem and progenitor cells (HSPC) from bone marrow.

Project description:The gene expression of bone marrow Hdc-/- and WT (LSK, Lin-c-kit+Sca-1+) hematopoetic stem and progenitor cells were isolated from Hdc-/- or WT mice. Cells were sorted by the cell surface markers of LSK total RNA was isolated from sorted 2,000 HSPCs using the ARCTURUS PicoPure RNA isolation kit (Life Technologies). cDNA was amplified and libraries were constructed by using the SMARTer Ultra Low Input RNA kit (Clontech Laboratories) and the Nextera XT DNA Library Preparation kit (Illumina) according to the respective manufacturer’s instructions. Sequencing was performed on the Illumina HiSeq2500 platform.

2019-04-09 | GSE80284 | GEO

Dysregulation of Wnt/β-Catenin Signaling pathway via RNF146 upregulation in the prefrontal cortex is responsible for social deficit in a VPA-induced ASD mouse model

Project description:Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder where patients have impaired social behavior, communication, repetitive behaviors, and restricted interest. Valproic acid (VPA) has been widely used to treat patients with epilepsy and bipolar disorder patients. However, VPA treatment during pregnancy has produced offspring with neurodevelopmental disorders, including ASD. To better understand the molecular function of ASD, we have used valproic acid, chemically induced ASD mice. We have performed LC-MS/MS analysis of VPA-induced offspring mice to the control to see the difference in their proteome difference. Our analysis showed that many neuronal network pathways were highly expressed in our differentially expressed proteins, and among them, Wnt/ β-catenin pathways showed clear enrichment. The RNF146 (E3 Ubiquitin-protein ligase) increase in VPA-exposed mice showed a highly significant effect on canonical Wnt/ β-catenin signaling pathways by disrupting the β-catenin destruction complex. The proteins like CREBBP, TCF4, and GSK3B also showed significant changes that indicate dysfunction of β-catenin destruction complex and activation of transcription factors.

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Expression profiles of 7-day cultured HSPCs in the presence or absence of valproic acid and/or lithium

Project description:Two small molecules, valproic acid (VPA) and lithium (Li), were tested to inhibit differentiation of hematopoietic stem/progenitor (HSPC) cells in culture. HSPCs exposed to VPA and Li during differentiation-inducing culture preserved an immature cell phenotype, provided radioprotection to lethally irradiated recipients and enhanced in vivo repopulating potential. Furthermore, VPA and Li synergistically preserved expression of stem cell-related genes and repressed genes involved in differentiation. Target genes were collectively co-regulated during normal hematopoietic differentiation. Additionally, transcription factor networks were identified as possible primary regulators. Our results demonstrate that the combination of VPA and Li potently prevents differentiation at the biological and the molecular level, and provide evidence to suggest that combinatorial screening of chemical compounds may uncover possible additive/synergistic effects to modulate stem cell fate decisions. These data consist of total mRNA obtained from hematopoietic cells cultured for 7 days in the presence or absence of valproic acid and/or lithium. All samples were analyzed in independent biological triplicates.

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Expression data from Bone marrow and Fetal liver Lineage-c-Kit+Sca-1+ (LSK) cells

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