Logical modeling of cell fate specification—Application to T cell commitment

Cacace, Elisabetta; Collombet, Samuel; Thieffry, Denis

doi:10.1016/bs.ctdb.2020.02.008

Cited by 7 publications

(5 citation statements)

References 85 publications

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“…TolDC are important in the immune response and are becoming relevant due to their possible usage as therapy in immune diseases (35)(36)(37). Logical models have been widely used to describe biological processes like T-cell commitment (38), cell death (39), cell interaction during infection (40), sex determination (41), etc. Our model describes the tolerization of monocytes and the principal participants of this commitment.…”

Section: Discussionmentioning

confidence: 99%

Logical model of human tolerogenic dendritic cells and their participation in autoimmune disease

Nuñez-Reza,

Lozano-Jiménez,

Martínez-Hernández

et al. 2023

Preprint

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Tolerogenic dendritic cells (tolDC) regulate the immune response, several clinical trials focused on autoimmune diseases use tolDC to promote immune tolerance response and Treg activation. Here we built a logical model for the tolerization cellular process of dendritic cells using IL10. By combining literature knowledge, microarray gene expression, and key tolDC markers, we ensembled a logical model that describes the obtention of tolDC using the IL10 signaling cascade that spawns the most tolerogenic phenotype. The model uses IL10 as input and the signaling cascade that trigger seven transcription factors (TFs), three previously known TFs in the IL10 response (STAT3, NFKB, STAT6), and four were incorporated based on our gene expression analysis (IRF8, TCF7L2, CEBPB, and TFCP2L1). Using our model, we generated mutants in-silico and identified that even when IL10 is present the single mutants for TCF7L2, IRF8, TFCP2L1, and STAT3 were not able to reach a tolDC stable state, highlighting the relevance of these TFs in the process. The current model sets a precedent that will help in the development of tolDC for future applications.

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Section: Discussionmentioning

confidence: 99%

Logical model of human tolerogenic dendritic cells and their participation in autoimmune disease

Nuñez-Reza,

Lozano-Jiménez,

Martínez-Hernández

et al. 2023

Preprint

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“…The current gene network model we present differs from previous versions (27,(69)(70)(71)(72)(73)(74) in several ways. In particular, initial models for early T-cell developmental GRNs were based primarily on candidate gene measurements, due to technical considerations.…”

Section: Construction Of An Updated T-cell Specification Grn Modelmentioning

confidence: 99%

Multi-modular structure of the gene regulatory network for specification and commitment of murine T cells

Shin

Rothenberg

2023

Front. Immunol.

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T cells develop from multipotent progenitors by a gradual process dependent on intrathymic Notch signaling and coupled with extensive proliferation. The stages leading them to T-cell lineage commitment are well characterized by single-cell and bulk RNA analyses of sorted populations and by direct measurements of precursor-product relationships. This process depends not only on Notch signaling but also on multiple transcription factors, some associated with stemness and multipotency, some with alternative lineages, and others associated with T-cell fate. These factors interact in opposing or semi-independent T cell gene regulatory network (GRN) subcircuits that are increasingly well defined. A newly comprehensive picture of this network has emerged. Importantly, because key factors in the GRN can bind to markedly different genomic sites at one stage than they do at other stages, the genes they significantly regulate are also stage-specific. Global transcriptome analyses of perturbations have revealed an underlying modular structure to the T-cell commitment GRN, separating decisions to lose “stem-ness” from decisions to block alternative fates. Finally, the updated network sheds light on the intimate relationship between the T-cell program, which depends on the thymus, and the innate lymphoid cell (ILC) program, which does not.

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“…The emergence of next generation sequencing and the amount of data generated have facilitated the study of molecular regulatory networks helping the construction of numerous logical models, among others related to hematopoiesis. These models have been useful in understanding regulatory events in hematopoiesis, such as those focused on T cell differentiation [117,118] and their activation [119], which have contributed to the understanding of cancer resistance to immunotherapies [120].…”

Section: Network-based Dynamic Modeling: a Successful Approach To Dec...mentioning

confidence: 99%

Single Cell Transcriptomics to Understand HSC Heterogeneity and Its Evolution upon Aging

Hérault

Poplineau

Rémy

et al. 2022

Cells

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Single-cell transcriptomic technologies enable the uncovering and characterization of cellular heterogeneity and pave the way for studies aiming at understanding the origin and consequences of it. The hematopoietic system is in essence a very well adapted model system to benefit from this technological advance because it is characterized by different cellular states. Each cellular state, and its interconnection, may be defined by a specific location in the global transcriptional landscape sustained by a complex regulatory network. This transcriptomic signature is not fixed and evolved over time to give rise to less efficient hematopoietic stem cells (HSC), leading to a well-documented hematopoietic aging. Here, we review the advance of single-cell transcriptomic approaches for the understanding of HSC heterogeneity to grasp HSC deregulations upon aging. We also discuss the new bioinformatics tools developed for the analysis of the resulting large and complex datasets. Finally, since hematopoiesis is driven by fine-tuned and complex networks that must be interconnected to each other, we highlight how mathematical modeling is beneficial for doing such interconnection between multilayered information and to predict how HSC behave while aging.

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Logical modeling of cell fate specification—Application to T cell commitment

Cited by 7 publications

References 85 publications

Logical model of human tolerogenic dendritic cells and their participation in autoimmune disease

Logical model of human tolerogenic dendritic cells and their participation in autoimmune disease

Multi-modular structure of the gene regulatory network for specification and commitment of murine T cells

Single Cell Transcriptomics to Understand HSC Heterogeneity and Its Evolution upon Aging

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