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Differential gene expression profiles between myeloid-biased and lymphoid-biased hematopoietic stem cells.

ABSTRACT: Array analysis of My-bi and Ly-bi HSC identifies candidate molecules for myeloid-bias. Collectively the data show that HSC in adults are largely epigenetically fixed in differentiation and self-renewal behavior. A direct examination of the epigenetic mechanisms that imprint HSC is difficult. However, an indirect way of assessing the effects of epigenetic imprinting is to look for the expressed gene programs of different types of HSC. Therefore, we performed an array analysis in collaboration with Dr. Michael Cooke. My-bi and Ly-bi HSC were identified in clonally repopulated hosts. The analysis returned 218 differentially expressed genes (≥ Log2 ≥2, p< 0.05) of which 36 were found to be overexpressed in My-bi HSC and the rest was overexpressed in Ly-bi HSC (Appendix A). There was no difference in expression levels for genes known to be involved in fate decisions during differentiation. This agrees well with our data that lineage bias is a stable function of a HSC, and does not reflect a differentiated type of cell.

ORGANISM(S): Mus musculus

PROVIDER: GSE41702 | GEO | 2013/05/01

SECONDARY ACCESSION(S): PRJNA177995

REPOSITORIES: GEO

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Differential gene expression profiles between myeloid-biased and lymphoid-biased hematopoietic stem cells.

Project description:Array analysis of My-bi and Ly-bi HSC identifies candidate molecules for myeloid-bias. Collectively the data show that HSC in adults are largely epigenetically fixed in differentiation and self-renewal behavior. A direct examination of the epigenetic mechanisms that imprint HSC is difficult. However, an indirect way of assessing the effects of epigenetic imprinting is to look for the expressed gene programs of different types of HSC. Therefore, we performed an array analysis in collaboration with Dr. Michael Cooke. My-bi and Ly-bi HSC were identified in clonally repopulated hosts. The analysis returned 218 differentially expressed genes (M-bM-^IM-% Log2 M-bM-^IM-%2, p< 0.05) of which 36 were found to be overexpressed in My-bi HSC and the rest was overexpressed in Ly-bi HSC (Appendix A). There was no difference in expression levels for genes known to be involved in fate decisions during differentiation. This agrees well with our data that lineage bias is a stable function of a HSC, and does not reflect a differentiated type of cell. Gene expression profiles of myeloid-biased (My-bi) and lymphoid-biased (Ly-bi) stem cells were analyzed. Clonally repopulated hosts were generated by limiting dilution of bone marrow into ablated hosts and lineage bias was determined. Single My-bi (Tenor) and Ly-bi (Mort) repopulated hosts were sacrificed and Donor type HSC were enriched for Sca-1+, Lin- cells. Two technical replicates of RNA extract were run from each clone.

2013-05-01 | E-GEOD-41702 | biostudies-arrayexpress

Lymphoid Biased Hematopoietic Stem Cells are Maintained with Age and Retain Normal Developmental Potential in the Absence of Inflammatory Stimuli

Project description:The hematopoietic stem cell (HSC) compartment includes lymphoid biased (Ly-HSCs) and myeloid biased (My-HSCs) subsets. Current models propose that the number of Ly-HSCs declines with age and this contributes to the diminution of lymphopoiesis that is a feature of aging. This view is based on a reduction in the frequency of Ly-HSCs in old bone marrow, but we now show that when total HSCs are taken into account, the number of Ly-HSCs is not reduced in old mice. We further demonstrate that old Ly-HSCs exhibit a normal capacity to produce lymphoid progenitors when removed from the bone marrow. However, the production of inflammatory cytokines is known to increase with age, and when Ly-HSCs are exposed to these mediators, lymphocyte production is blocked. We also demonstrate that old Ly-HSCs generate myeloid cells that phenotypically resemble those produced by old My-HSCs, a finding consistent with the myeloid biased gene expression pattern of old Ly-HSCs. These observations indicate that current models of how aging impacts the lymphopoietic potential of HSCs need to be revised and point to changes in the in vivo environment, rather than intrinsic changes in HSCs, as the principal cause of the reduced lymphopoiesis and increased myelopoiesis during aging.

2019-02-21 | GSE112769 | GEO

Expression data from side population subfraction hematopoietic stem cells

Project description:The traditional view of hematopoiesis has been that all the cells of the peripheral blood are the progeny of a unitary homogeneous pool of hematopoietic stem cells (HSCs). Recent evidence suggests that the hematopoietic system is actually maintained by a consortium of HSC subtypes with distinct functional characteristics. We show here that myeloid-biased HSCs (My-HSCs) and lymphoid-biased (Ly-HSCs) can be purified according to their capacity for Hoechst dye efflux in combination with canonical HSC markers. We used microarray expression profiling to determine the transcriptional profiles of myeloid-biased lower-SP HSCs and lymphoid-biased upper-SP HSCs

2010-03-01 | GSE16475 | GEO

Expression data from side population subfraction hematopoietic stem cells

2010-03-06 | E-GEOD-16475 | biostudies-arrayexpress

Distinct imprinting signatures and biased differentiation of human androgenetic and parthenogenetic embryonic stem cells [microarray]

Project description:Genomic imprinting is an epigenetic mechanism that results in parent-of-origin monoallelic expression of specific genes, which precludes uniparental development and underlies various diseases. Here we explored molecular and developmental aspects of imprinting in humans by generating exclusively-paternal human androgenetic embryonic stem cells (aESCs) and comparing them with exclusively-maternal parthenogenetic ESCs (pESCs) and bi-parental ESCs, establishing a pluripotent-cell system of distinct parental backgrounds. Analyzing the transcriptomes and methylomes of human aESCs, pESCs and bi-parental ESCs enabled the characterization of regulatory relations at known imprinted regions and uncovered new imprinted gene candidates within and outside known imprinted regions. Investigating the consequences of uniparental differentiation, we showed the known paternal-genome preference for placental contribution, revealed a novel bias towards liver differentiation, and implicated the involvement of the imprinted gene IGF2 in this process. Our results demonstrate the utility of parent-specific human ESCs for dissecting the role of imprinting in human development and disease.

2019-09-05 | GSE114676 | GEO

Distinct imprinting signatures and biased differentiation of human androgenetic and parthenogenetic embryonic stem cells [RNA-Seq II]

Project description:Genomic imprinting is an epigenetic mechanism that results in parent-of-origin monoallelic expression of specific genes, which precludes uniparental development and underlies various diseases. Here, we explored molecular and developmental aspects of imprinting in humans by generating exclusively paternal human androgenetic embryonic stem cells (aESCs) and comparing them with exclusively maternal parthenogenetic ESCs (pESCs) and bi-parental ESCs, establishing a pluripotent cell system of distinct parental backgrounds. Analyzing the transcriptomes and methylomes of human aESCs, pESCs, and bi-parental ESCs enabled the characterization of regulatory relations at known imprinted regions and uncovered imprinted gene candidates within and outside known imprinted regions. Investigating the consequences of uniparental differentiation, we showed the known paternal-genome preference for placental contribution, revealed a similar bias toward liver differentiation, and implicated the involvement of the imprinted gene IGF2 in this process. Our results demonstrate the utility of parent-specific human ESCs for dissecting the role of imprinting in human development and disease.

2019-09-05 | GSE114677 | GEO

Distinct imprinting signatures and biased differentiation of human androgenetic and parthenogenetic embryonic stem cells [RNA-Seq I]

Project description:Genomic imprinting is an epigenetic mechanism that results in parent-of-origin monoallelic expression of specific genes, which precludes uniparental development and underlies various diseases. Here, we explored molecular and developmental aspects of imprinting in humans by generating exclusively paternal human androgenetic embryonic stem cells (aESCs) and comparing them with exclusively maternal parthenogenetic ESCs (pESCs) and bi-parental ESCs, establishing a pluripotent cell system of distinct parental backgrounds. Analyzing the transcriptomes and methylomes of human aESCs, pESCs, and bi-parental ESCs enabled the characterization of regulatory relations at known imprinted regions and uncovered imprinted gene candidates within and outside known imprinted regions. Investigating the consequences of uniparental differentiation, we showed the known paternal-genome preference for placental contribution, revealed a similar bias toward liver differentiation, and implicated the involvement of the imprinted gene IGF2 in this process. Our results demonstrate the utility of parent-specific human ESCs for dissecting the role of imprinting in human development and disease.

2019-09-05 | GSE114678 | GEO

IL-2Rα-biased, but not βγ-biased, agonist reprograms tumor immune landscape and synergize with αPD-1 therapy

Project description:We investigated whether exogenous supplies of different IL-2R agonists (IL-2wt, IL-2nα or IL-2α-bias) at the concentration of 3 mg/g body weight could rescue the transcriptional signatures of dysfunctional T cells in large tumors, or allow them to regain sensitivity to αPD-1 antibody. Remarkably, after transient stimulation by IL-2wt, large tumors fully restored the effector/activation signatures observed in small tumors, such as upregulation of effector genes (Gzma, Gzmb, Gzmk and Ifng), T cell activation/exhaustion genes (Ctla4, Pdcd1, Lag3 and Havcr2), inflammatory cytokine/cytokine receptors (Il2ra, Il2rb, Il2rg and Il21r), and chemokines (Cxcl9, Cxcl10 and Ccl19) (Fig.7d). Surprisingly, although IL-2α-bias had >10-fold weaker in vitro activity than IL-2wt, and could only activate the small fraction of CD25-upregulated CD8+Teff cells, the transcriptional profiles were indistinguishable between IL-2wt and IL-2α-bias treated large tumors. In stark contrast, IL-2nα treatment showed no meaningful transcriptional changes in large tumors compared to untreated control. These results once again demonstrate the critical role of CD25 in transmitting IL-2 signaling to reprogram the tumor immune microenvironment.

2023-04-02 | E-MTAB-12372 | biostudies-arrayexpress

Bulk and single RNA sequencing on the role of Igf2bp2 in myeloid-biased HSC

Project description:Using RNA sequencing analysis on myeloid biased HSC, we compared gene expression profiles between WT and Igf2bp2 knock-out mice at young and old age. 1421 differentially expressed genes were identified in young myeloid biased HSC from Igf2bp2 knock-out mice compared to young WT; however, only 26 differentially expressed genes were identified in old myeloid biased HSC from Igf2bp2 knock-out mice compared to old WT. Compared to young WT myeloid biased HSC, myeloid biased HSC from young Igf2bp2 knock-out exhibits reduced expression of genes involved in metabolism and translation. In addition, single cell RNA sequencing analysis of myeloid biased HSC in young wildtype mice identified nine sub-clusters. HSCs from a sub-cluster with high expression of Igf2bp2 exhibit up-regulated IGF/PI3K/AKT signaling and increased expression of genes involved in HSC quiescence and maintenance. Altogether, the study provides a correlation and mechanism to understand the role of Igf2bp2 in HSC function and aging.

2021-02-05 | GSE166176 | GEO

RNAseq analysis of murine ITPKB deficient versus wild type LT-HSC

Project description:Tight regulation of hematopoietic stem cell (HSC) homeostasis is essential for life-long hematopoiesis, for preventing blood cancers and for averting bone marrow failure. The underlying mechanisms are incompletely understood. Here, we identify production of inositol-tetrakisphosphate (IP4) by inositoltrisphosphate 3-kinase B (ItpkB) as essential for HSC quiescence and function. Young ItpkB-/- mice accumulated phenotypic HSC and showed extramedullary hematopoiesis. ItpkB-/- HSC were less quiescent and proliferated more than wildtype controls. They downregulated quiescence and stemness associated mRNAs, but upregulated activation, oxidative metabolism, protein synthesis and lineage associated transcripts. Although they showed no significant homing defects, ItpkB-/- HSC had a severely reduced competitive long-term repopulating potential. Aging ItpkB-/- mice lost hematopoietic stem and progenitor cells and died with severe anemia. Wildtype HSC normally repopulated ItpkB-/- hosts, incidating a HSC-intrinsic ItpkB requirement. ItpkB-/- HSC had reduced cobblestone-area forming cell activity in vitro and showed increased stem-cell-factor activation of the phosphoinositide 3-kinase (PI3K) effector Akt, reversed by exogenous provision of the known PI3K/Akt antagonist IP4. They also showed transcriptome changes consistent with hyperactive Akt/mTOR signaling. Thus, we propose that ItpkB ensures HSC quiescence by limiting cytokine-induced PI3K signaling in HSC.

2015-03-31 | GSE56613 | GEO

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