Dynamic equilibrium of heterogeneous and interconvertible multipotent hematopoietic cell subsets

Weston, Wendy; Zayas, Jennifer; Pérez, Ruben Esteban; George, John E.; Jurecic, Roland

doi:10.1038/srep05199

Cited by 10 publications

(12 citation statements)

References 60 publications

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“…6A). This result reveals cell plasticity in population dynamics based on the proposed model, quantitatively explain the phenomena of dynamic equilibrium in stem cell regenerations [5,26,39,68].…”

Section: Rongsheng Huang and Jinzhi Leisupporting

confidence: 61%

Cell-Type Switches Induced by Stochastic Histone Modification Inheritance

Huang

Lei

2018

Preprint

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Cell plasticity is important for tissue developments during which somatic cells may switch between distinct states. Genetic networks to yield multistable states are usually required to yield multiple states, and either external stimuli or noise in gene expressions are trigger signals to induce cell-type switches between the states. In many biological systems, cells show highly plasticity and can switch between different state spontaneously, but maintaining the dynamic equilibrium of the cell population. Here, we considered a mechanism of spontaneous cell-type switches through the combination between gene regulation network and stochastic epigenetic state transitions. We presented a mathematical model that consists of a standard positive feedback loop with changes of histone modifications during with cell cycling. Based on the model, nucleosome state of an associated gene is a random process during cell cycling, and hence introduces an inherent noise to gene expression, which can automatically induce cell-type switches in cell cycling. Our model reveals a simple mechanism of spontaneous cell-type switches through a stochastic histone modification inheritance during cell cycle. This mechanism is inherent to the normal cell cycle process, and is independent to the external signals.2010 Mathematics Subject Classification. Primary: 92B05, 91B70; Secondary : 92D25. 1 2 RONGSHENG HUANG AND JINZHI LEI changes in the activities of regulators in the gene regulation network is one of the driving force to induce cell type switch, e.g., stem cell differentiation [10,23,24,42]. During development, cells undergo a unidirectional course of differentiation, which can be viewed as a dynamical process on the Waddington epigenetic landscape with multistable states, the input signals can change the landscape to guide the transition between different states [15,19,72].Chromatin regulators play crucial roles in establishing and maintaining gene expression states [4,30]. Histone modifications and DNA methylations are important epigenetic states that can regulate the chromatin state of a DNA sequence, and modulate the gene expression dynamics. These epigenetic modifications are modulated by intercellular enzyme activities, and hence dynamically change over time and during cell cycle [50]. The stochastic epigenetic inheritance during cell cycle can result in spontaneous alteration of epigenetic state during development; epigenetic changes in regulatory loci often correlate with expression changes during stem cell differentiation [3,8,27,58,73].Here, to investigate how stochastic epigenetic inheritance affect the dynamical process of cell fate decision, we studied a computational model that combines positive feedback regulation with histone modification of the gene promoter. Moreover, cell cycle was included in the model through the stochastic inheritance during cell cycle. We show that the dynamic behavior of histone modification in the cell division can induce spontaneous cell-type switches during normal development process, from which t...

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Section: Rongsheng Huang and Jinzhi Leisupporting

confidence: 61%

Cell-Type Switches Induced by Stochastic Histone Modification Inheritance

Huang

Lei

2018

Preprint

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“…In competitive transplantation assays, the reconstitution capability of Prmt5 D/D HSCs was severely compromised (Figures 1D and 1E). We confirmed the requirement for PRMT5 activity in HSCs using the multipotent, stem cell factor (SCF)-dependent murine hematopoietic cell line EML, which is recognized as an in vitro surrogate for primary HSPCs (Weston et al, 2014). Using the well-characterized PRMT5 inhibitor EPZ015666 (Chan-Penebre et al, 2015), we depleted PRMT5 activity in EML cells ( Figure 1F), which led to a corresponding decrease in EML cell proliferation and viability, particularly for concentrations R 5 mM ( Figures 1G and 1H).…”

Section: Hsc Maintenance Requires Cell-intrinsic Prmt5 Activitymentioning

confidence: 56%

PRMT5 Modulates Splicing for Genome Integrity and Preserves Proteostasis of Hematopoietic Stem Cells

et al. 2019

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Graphical AbstractHighlights d HSC size and protein synthesis rate increase upon depletion of PRMT5 activity d PRMT5 depletion leads to AKT/mTOR activation, which partly contributes to HSC loss d PRMT5 activity is required for splicing of DNA repair genes in multiple cell types d PRMT5 KO or inhibition causes oxidative DNA damage that triggers p53-induced apoptosis SUMMARY Protein arginine methyltransferase 5 (PRMT5) is essential for hematopoiesis, while PRMT5 inhibition remains a promising therapeutic strategy against various cancers. Here, we demonstrate that hematopoietic stem cell (HSC) quiescence and viability are severely perturbed upon PRMT5 depletion, which also increases HSC size, PI3K/AKT/mechanistic target of rapamycin (mTOR) pathway activity, and protein synthesis rate. We uncover a critical role for PRMT5 in maintaining HSC genomic integrity by modulating splicing of genes involved in DNA repair. We found that reducing PRMT5 activity upregulates exon skipping and intron retention events that impair gene expression. Genes across multiple DNA repair pathways are affected, several of which mediate interstrand crosslink repair and homologous recombination. Consequently, loss of PRMT5 activity leads to endogenous DNA damage that triggers p53 activation, induces apoptosis, and culminates in rapid HSC exhaustion, which is significantly delayed by p53 depletion. Collectively, these findings establish the importance of cell-intrinsic PRMT5 activity in HSCs.

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“…Dynamic equilibrium of sub-states of stem cells is observed not only in the EMT system, but also in hematopoietic and embryonic stem cell populations [11] [27] [34]. Moreover, it was suggested that heterogeneity of cell population might be related to disseminated cancer cell dormancy [28].…”

Section: Discussionmentioning

confidence: 99%

Controlling stochasticity in epithelial-mesenchymal transition through multiple intermediate cellular states

Ta¹,

Nie²,

Hong³

2016

DCDS-B

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Epithelial-mesenchymal transition (EMT) is an instance of cellular plasticity that plays critical roles in development, regeneration and cancer progression. Recent studies indicate that the transition between epithelial and mesenchymal states is a multi-step and reversible process in which several intermediate phenotypes might coexist. These intermediate states correspond to various forms of stem-like cells in the EMT system, but the function of the multi-step transition or the multiple stem cell phenotypes is unclear. Here, we use mathematical models to show that multiple intermediate phenotypes in the EMT system help to attenuate the overall fluctuations of the cell population in terms of phenotypic compositions, thereby stabilizing a heterogeneous cell population in the EMT spectrum. We found that the ability of the system to attenuate noise on the intermediate states depends on the number of intermediate states, indicating the stem-cell population is more stable when it has more sub-states. Our study reveals a novel advantage of multiple intermediate EMT phenotypes in terms of systems design, and it sheds light on the general design principle of heterogeneous stem cell population.

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Dynamic equilibrium of heterogeneous and interconvertible multipotent hematopoietic cell subsets

Cited by 10 publications

References 60 publications

Cell-Type Switches Induced by Stochastic Histone Modification Inheritance

Cell-Type Switches Induced by Stochastic Histone Modification Inheritance

PRMT5 Modulates Splicing for Genome Integrity and Preserves Proteostasis of Hematopoietic Stem Cells

Controlling stochasticity in epithelial-mesenchymal transition through multiple intermediate cellular states

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