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A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis independent role for p53 in self-renewal

ABSTRACT: Analysis of differentially expressed genes in human Cord Blood cells cultured for 4 days and sorted into CD34+CD90+ and CD34+CD90- fractions. The objective for the experiment was to identify genes related to p53 and DNA damage response pathways

ORGANISM(S): Homo sapiens

PROVIDER: GSE21830 | GEO | 2010/06/29

SECONDARY ACCESSION(S): PRJNA126909

REPOSITORIES: GEO

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A distinctive DNA damage response in human hematopoietic stem cells reveals an apoptosis independent role for p53 in self-renewal

Project description:Analysis of differentially expressed genes in human Cord Blood cells cultured for 4 days and sorted into CD34+CD90+ and CD34+CD90- fractions. The objective for the experiment was to identify genes related to p53 and DNA damage response pathways Total RNA was isolated from at least 10000 cells after 4 days of culture and sorting

2010-07-29 | E-GEOD-21830 | biostudies-arrayexpress

Precise Gene Editing Preserves Hematopoietic Stem Cell Function Following Transient p53-Mediate DNA Damage Response [scRNA-seq]

Project description:We performed single-cell (sc)RNA-Seq on male donors FACS-sorted “primitive” (CD34+ CD133+ CD90+) and “progenitor” (CD34+ CD133+ CD90-) HSPC cells treated with IL2RG ZFN, High Specificity (HS), (Low Specificity (LS) or control RNP in a ratio 1 to 1. We also included HS RNP and the cognate repair template containing a GFP expression cassette delivered by AAV6 and sorted for targeted integration (HS/AAV6 GFP+ vs. HS/AAV6 GFP-)

2019-03-01 | GSE119594 | GEO

Single Cell analysis of the two Human Hematopoietic Stem Cell Populations

Project description:Single cell transcriptomic profiling (sc RNA-seq) of the two Human Hematopoietic Stem Cell Populations: CD34+CD38-CD45RA-CD90+CD49f+ (hereafter CD90+CD49f+) and CD34+CD38-CD45RA-CD90-CD49f+ (hereafter CD90-CD49f+)

2021-07-01 | GSE154931 | GEO

Cereblon attenuates DNA damage-induced apoptosis by regulating the transcription-independent function of p53.

Project description:Cereblon (CRBN) is the substrate receptor of the cullin 4-RING E3 ligase complex and has been employed for targeted protein degradation in the treatment of cancers. However, its normal physiological functions and molecular mechanism in the regulation of DNA damage response are largely unknown. Here we find that CRBN plays a protective role against DNA damage-induced apoptosis in cell lines and primary cells. Mechanistic studies demonstrate that although CRBN does not affect the ubiquitination and degradation of the tumor suppressor p53, it directly interacts with p53 and therefore, suppresses the interaction between p53 and anti-apoptotic regulators Bcl-2 and Bcl-XL. CRBN depletion enhances the interaction between p53 and Bcl-2/Bcl-XL, reduces mitochondrial membrane potential, increases the cleavage of caspase-3 and poly(ADP-ribose) polymerase 1, and thus promotes DNA damage-induced apoptosis in cell lines and primary cells upon etoposide treatment. Moreover, Crbn knockout mice exhibit increased mortality upon etoposide challenge. Taken together, our data elucidate a novel molecular mechanism by which CRBN inhibits DNA damage response in vitro and in vivo. This work extends our understanding of the broad spectrum of physiological roles for CRBN and may suggest its potential application in the treatment of DNA damage-associated diseases.

| S-EPMC6347596 | biostudies-literature

Functional and transcriptional heterogeneity of human hemopoietic lympho-myeloid progenitors

Project description:Cord blood (CB) samples from normal donors were obtained with informed consent. Fresh CB samples were processed within 18-34h after collection. Mononuclear cells were isolated and CD34+ fraction was separated. CB CD34+ enriched fraction was lineage depleted by staining with purified anti-human CD2, CD3, CD4, CD7, CD8a, CD11b, CD14, CD19, CD20, CD56, CD235a followed by Qdot 605 conjugated goat F(ab')2 anti-mouse IgG (H+L). Cells were also stained with anti-human CD38-FITC, CD45RA-PE or -BV650, CD123-PE Cy7, CD90-biotin, CD34- PerCP and CD10-APC. Finally, cells were incubated with streptavidin-conjugated APC-eF780 and Hoechst 33258 (Invitrogen, final concentration: 1 g/ml). Populations were defined, as follows: HSC - Lin-CD34+CD38-CD90+CD45RA-CD10-, MPP - Lin-CD34+CD38-CD90-CD45RA-CD10-, LMPP - Lin-CD34+CD38-CD90-/loCD45RA+CD10-, MLP - Lin-CD34+CD38-CD90-/loCD45RA+CD10+, GMP - Lin-CD34+CD38+CD123+CD45RA+CD10-, CMP - Lin-CD34+CD38+CD123+CD45RA-CD10-, MEP - Lin-CD34+CD38+CD123-CD45RA-CD10-.

2017-10-03 | E-MTAB-5456 | biostudies-arrayexpress

p53 inactivation unmasks histone methylation-independent WDR5 functions that drive self-renewal and differentiation of pluripotent stem cells.

Project description:p53 alterations occur during culture of pluripotent stem cells (PSCs), but the significance of these events on epigenetic control of PSC fate determination remains poorly understood. Wdr5 deletion in p53-null (DKO) mouse ESCs (mESCs) leads to impaired self-renewal, defective retinal neuroectoderm differentiation, and de-repression of germ cell/meiosis (GCM)-specific genes. Re-introduction of a WDR5 mutant with defective H3K4 methylation activity into DKO ESCs restored self-renewal and suppressed GCM gene expression but failed to induce retinal neuroectoderm differentiation. Mechanistically, mutant WDR5 targets chromatin that is largely devoid of H3K4me3 and regulates gene expression in p53-null mESCs. Furthermore, MAX and WDR5 co-target lineage-specifying chromatin and regulate chromatin accessibility of GCM-related genes. Importantly, MAX and WDR5 are core subunits of a non-canonical polycomb repressor complex 1 responsible for gene silencing. This function, together with canonical, pro-transcriptional WDR5-dependent MLL complex H3K4 methyltransferase activity, highlight how WDR5 mediates crosstalk between transcription and repression during mESC fate choice.

| S-EPMC8581203 | biostudies-literature

Expression profiling of purified hematopoietic stem cells from patients with MDS and healthy controls

Project description:Gene expression analysis on purified human long-term hematopoietic stem cells (LT-HSC; CD34+CD38-CD90+) and short-term HSC (ST-HSC; CD34+CD38-CD90-) derived from healthy control patients and patients with myelodysplastic syndrome (MDS)

2012-08-01 | GSE38955 | GEO

Inhibition of the p53 E3 ligase HDM-2 induces apoptosis and DNA damage--independent p53 phosphorylation in mantle cell lymphoma.

Project description:The ubiquitin-proteasome pathway has been validated as a target in non-Hodgkin's lymphoma through demonstration of the activity of the proteasome inhibitor bortezomib.Another potentially attractive target is the human homologue of the murine double minute-2 protein, HDM-2, which serves as the major p53 E3 ubiquitin ligase; we therefore evaluated the activity of a novel agent, MI-63, which disrupts the HDM-2/p53 interaction.Treatment of wild-type p53 mantle cell lymphoma (MCL) cell lines with MI-63 resulted in a dose- and time-dependent inhibition of proliferation, with an IC(50) in the 0.5 to 5.0 micromol/L range. MI-63 induced p53 and HDM-2 accumulation, as well as other downstream p53 targets such as p53 up-regulated modulator of apoptosis and p21(Cip1). This was associated with cell cycle arrest at G(1)-S; activation of caspase-3, caspase-8, and caspase-9; cleavage of poly-(ADP-ribose) polymerase; and loss of E2F1. HDM-2 inhibition caused phosphorylation of p53 at multiple serine residues, including 15, 37, and 392, which coincided with low levels of DNA strand breaks. DNA damage occurred in a small percentage of cells and did not induce phosphorylation of the DNA damage marker H2A.X(Ser139). Combinations of MI-63 with the molecularly targeted agents bortezomib and rapamycin showed synergistic, sequence-dependent antiproliferative effects. Treatment of primary MCL patient samples resulted in apoptosis and induction of p53 and p21, which was not seen in normal controls.These findings support the hypothesis that inhibition of the HDM-2/p53 interaction may be a promising approach both by itself and in combination with currently used chemotherapeutics against lymphoid malignancies.

| S-EPMC2576518 | biostudies-literature

RNA Sequencing of LT-HSCs and ST-HSCs from healthy adult human Bone Marrow

Project description:The transcriptome of LT-HSC (CD34+CD38-CD45RA+CD90+CD49f+) and ST-HSC (CD34+CD38-CD45RA+CD90-CD49f-) from healthy adult human Bone Marrow Cells were assessed by RNA-seq.

2022-04-06 | E-MTAB-9892 | biostudies-arrayexpress

Newly defined human hematopoietic stem cell populations

Project description:Transcriptomic profiling (RNA-seq) of primitive human progenitor populations CD34+CD38-CD45RA-CD90-EPCR-; hereafter CD90-EPCR- MPP.

2022-02-23 | GSE197079 | GEO

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