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Complex Gene Regulatory Networks – from Structure to Biological Observables: Cell Fate Determination

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Abbreviations

Transcription factor:

A protein that binds to the regulatory region of a target gene (its promoter or enhancer regions) and thereby, controls its expression (transcription of the target gene into a mRNA which is ultimately translated into the protein encoded by the target gene). Transcription factors account for temporal and contextual specificity of the expression of genes; for instance, a developmentally regulated gene is expressed only during a particular phase in development and in particular tissues.

Gene regulatory network (GRN):

Transcription factors regulate the expression of other transcription factor genes as well as other ‘non‐regulatory’ genes which encode proteins, such as metabolic enzymes or structural proteins. A regulatory relationship between two genes thus is formalized as: “transcription factor A is the regulator of target gene B” or: A → B. The entirety of such regulatory interactions forms a network = the gene regulatory network (GRN). Synonyms: genetic network or gene network, transcriptional network.

Gene network architecture and topology:

The GRN can be represented as a “directed graph”. The latter consists of a set of nodes (= vertices) representing the genes connected by arrows (directed links or edges) representing the regulatory interactions pointing from the regulator to the regulated target gene. [In contrast, in an undirected graph, the links are simple lines without arrowheads. The protein‐interaction network can be represented as undirected graph]. The topology of a network is the structure of this graph and is an abstract notation, without physicality, of all the potential regulatory interactions between the genes. Topology usually is used to denote the simple interactions captured by the directed graph. For defining the network dynamics, however, additional aspects of interactions need to be specified, including: modalities or “sign” of an arrow (inhibitory vs. activating regulation), the ‘transfer functions’ (relationship between magnitude of input to that of the output = target gene) and the logical function (notably, in Boolean network, defining how multiple inputs are related to each other and are integrated to shaping the output). In this article when all this additional information is implied to be included, the term gene network architecture is used. Thus, the graph topology is a subset of network architecture.

Gene network dynamics:

The collective change of the gene expression levels of the genes in a network, essentially, the change over time of the network state S.

State space:

Phase space = the abstract space that contains all possible states S of a dynamical system. For (autonomous) gene regulatory networks, each state S is specified by the configuration of the expression levels of each of the N genes of the network; thus a system state S is one point in the N‑dimensional state space. As the system changes its state over time, S moves along trajectories in the state space.

Transcriptome:

Gene expression pattern across the entire (or large portion of) the genome, measured at the level of mRNA levels. Used as synonym to “gene expression profile”. The transcriptome can in a first approximation be considered a snapshot of the network state S of the GRN in gene network dynamics.

Cell type:

A distinct, whole-cell phenotype characteristic of a mature cell specialized to exert an organ‐specific function. Example of cell types are: liver cell, red blood cell, skin fibroblast, heart muscle cell, fat cell, etc. Cell types are characterized by their distinct cell morphology and their gene expression pattern.

Cell fate:

A potential developmental outcome of a (stem or progenitor) cell. A cell fate of a stem cell can be the development into a particular mature cell type.

Multipotency:

The ability of a cell to generate multiple cell types; a hallmark of stem cells. Stem cells are said to be multipotent (see also under Stem cells).

Stem cell:

A multi‐potent cell capable of “self‐renewal” (division in which both daughter cells have the same degree of multi‐potency as the mother cell) and can give rise to multiple cell types. There is a hierarchy of multipotency: a toti‐potent embryonic stem cell can generate all possible cell types in the body, including extra‐embryonic tissues, such as placenta. A pluripotent embryonic stem cell can generate tissues of three germ layers, i. e., it can produce all cell types of the foetus and the adult. A multipotent (sensu stritiore) stem cell of a tissue (e. g., blood) can give rise to all cell types of that tissue (e. g., a hematopoietic stem cell can produce all the blood cells). A multipotent progenitor cell can give rise to more than one cell types within a tissue (e. g. the granulocyte‐monocyte progenitor cell).

Cell lineage:

Developmental trajectory of a multipotent cell towards one of multiple cell types, e. g., the “myeloid lineage” among blood cells, comprising the white blood cells granulocytes, monocytes, etc. Thus, a cell fate decision is a decision between multiple lineages accessible to a stem or progenitor cell.

Differentiation:

The process of cell fate decision in a stem or progenitor cell and the subsequent maturation into a mature cell type.

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    Sui Huang & Stuart A. Kauffman

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Huang, S., Kauffman, S.A. (2009). Complex Gene Regulatory Networks – from Structure to Biological Observables: Cell Fate Determination . In: Meyers, R. (eds) Encyclopedia of Complexity and Systems Science. Springer, New York, NY. https://doi.org/10.1007/978-0-387-30440-3_79

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