Dataset Information

Drugs modulating stochastic gene expression affect the erythroid differentiation process.

ABSTRACT: To better understand the mechanisms behind cells decision-making to differentiate, we assessed the influence of stochastic gene expression (SGE) modulation on the erythroid differentiation process. It has been suggested that stochastic gene expression has a role in cell fate decision-making which is revealed by single-cell analyses but studies dedicated to demonstrate the consistency of this link are still lacking. Recent observations showed that SGE significantly increased during differentiation and a few showed that an increase of the level of SGE is accompanied by an increase in the differentiation process. However, a consistent relation in both increasing and decreasing directions has never been shown in the same cellular system. Such demonstration would require to be able to experimentally manipulate simultaneously the level of SGE and cell differentiation in order to observe if cell behavior matches with the current theory. We identified three drugs that modulate SGE in primary erythroid progenitor cells. Both Artemisinin and Indomethacin decreased SGE and reduced the amount of differentiated cells. On the contrary, a third component called MB-3 simultaneously increased the level of SGE and the amount of differentiated cells. We then used a dynamical modelling approach which confirmed that differentiation rates were indeed affected by the drug treatment. Using single-cell analysis and modeling tools, we provide experimental evidence that, in a physiologically relevant cellular system, SGE is linked to differentiation.

SUBMITTER: Guillemin A

PROVIDER: S-EPMC6872177 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Drugs modulating stochastic gene expression affect the erythroid differentiation process.

Guillemin Anissa A Duchesne Ronan R Crauste Fabien F Gonin-Giraud Sandrine S Gandrillon Olivier O

PloS one 20191121 11

To better understand the mechanisms behind cells decision-making to differentiate, we assessed the influence of stochastic gene expression (SGE) modulation on the erythroid differentiation process. It has been suggested that stochastic gene expression has a role in cell fate decision-making which is revealed by single-cell analyses but studies dedicated to demonstrate the consistency of this link are still lacking. Recent observations showed that SGE significantly increased during differentiatio ...[more]

PMID: 31751364

Similar Datasets

Project description:BackgroundThe guanine nucleotide binding protein (G protein)-coupled receptors (GPCRs) regulate cell growth, proliferation and differentiation. G proteins are also implicated in erythroid differentiation, and some of them are expressed principally in hematopoietic cells. GPCRs-linked NO/cGMP and p38 MAPK signaling pathways already demonstrated potency for globin gene stimulation. By analyzing erythroid progenitors, derived from hematopoietic cells through in vitro ontogeny, our study intends to determine early markers and signaling pathways of globin gene regulation and their relation to GPCR expression.ResultsHuman hematopoietic CD34+ progenitors are isolated from fetal liver (FL), cord blood (CB), adult bone marrow (BM), peripheral blood (PB) and G-CSF stimulated mobilized PB (mPB), and then differentiated in vitro into erythroid progenitors. We find that growth capacity is most abundant in FL- and CB-derived erythroid cells. The erythroid progenitor cells are sorted as 100% CD71+, but we did not find statistical significance in the variations of CD34, CD36 and GlyA antigens and that confirms similarity in maturation of studied ontogenic periods. During ontogeny, beta-globin gene expression reaches maximum levels in cells of adult blood origin (176 fmol/μg), while gamma-globin gene expression is consistently up-regulated in CB-derived cells (60 fmol/μg). During gamma-globin induction by hydroxycarbamide, we identify stimulated GPCRs (PTGDR, PTGER1) and GPCRs-coupled genes known to be activated via the cAMP/PKA (ADIPOQ), MAPK pathway (JUN) and NO/cGMP (PRPF18) signaling pathways. During ontogeny, GPR45 and ARRDC1 genes have the most prominent expression in FL-derived erythroid progenitor cells, GNL3 and GRP65 genes in CB-derived cells (high gamma-globin gene expression), GPR110 and GNG10 in BM-derived cells, GPR89C and GPR172A in PB-derived cells, and GPR44 and GNAQ genes in mPB-derived cells (high beta-globin gene expression).ConclusionsThese results demonstrate the concomitant activity of GPCR-coupled genes and related signaling pathways during erythropoietic stimulation of globin genes. In accordance with previous reports, the stimulation of GPCRs supports the postulated connection between cAMP/PKA and NO/cGMP pathways in activation of γ-globin expression, via JUN and p38 MAPK signaling.

Dataset Information

Drugs modulating stochastic gene expression affect the erythroid differentiation process.

Publications

Drugs modulating stochastic gene expression affect the erythroid differentiation process.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets