scholarly journals The Population Genetics of Gene Regulatory Networks

2021 ◽  
Author(s):  
Chia-Hung Yang ◽  
Samuel V. Scarpino
Keyword(s):  
Gene Regulatory Networks ◽  
Population Genetic ◽  
Regulatory Networks ◽  
Genetic Model ◽  
Structural Characteristics ◽  
Mechanistic Explanation ◽  
Eigenvector Centrality ◽  
Evolutionary Forces ◽  
Molecular Interaction Networks ◽  
Gene Regulatory

The evolution of diverse phenotypes both involves and is constrained by molecular interaction networks. When these networks influence patterns of expression, we refer to them as gene regulatory networks (GRNs). Here, we develop a population genetic model of GRN evolution. With this model, we prove that–across a broad spectrum of viability and mutation functions–the dynamics converge to a stationary distribution over GRNs. Next, we show from first principles how the frequency of GRNs at equilibrium will be proportional to each GRN’s eigenvector centrality in the genotype network. Finally, we determine the structural characteristics of GRNs that are favored in response to a range of selective environments and mutational constraints. Our work connects GRN evolution to population genetic models, and thus can provide a mechanistic explanation for the topology of GRNs experiencing various evolutionary forces.

scholarly journals TNF signalling fine-tunes Langerhans cell transcriptional programmes mediating adaptive immunity

2021 ◽  
Author(s):  
James Davies ◽  
Andres F. Vallejo ◽  
Sofia Sirvent ◽  
Gemma Porter ◽  
Kalum Clayton ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Immune Responses ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Mechanistic Explanation ◽  
Molecular Switches ◽  
Toggle Switch ◽  
Dense Network ◽  
Gene Regulatory ◽  
Combinatorial Interactions

ABSTRACTLangerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels, coordinating both immunogenic and tolerogenic immune responses. To determine molecular switches directing induction of LC immune activation, we performed mathematical modelling of gene regulatory networks identified by single cell RNA sequencing of LCs exposed to TNF, a key pro-inflammatory signal produced by the skin. Our approach delineated three programmes of LC phenotypic activation (immunogenic, tolerogenic or ambivalent), and confirmed that TNF enhanced LC immunogenic programming. Through regulon analysis followed by mutual information modelling, we identified IRF1 as the key transcription factor for the regulation of immunogenicity in LCs. Application of a mathematical toggle switch model, coupling IRF1 with tolerance-inducing transcription factors, determined the key set of transcription factors regulating the switch between tolerance and immunogenicity, and correctly predicted LC behaviour in LCs derived from different body sites. Our findings provide a mechanistic explanation of how combinatorial interactions between different transcription factors can coordinate specific transcriptional programmes in human LCs, interpreting the microenvironmental context of the local tissue microenvironments.

scholarly journals An IRF1-IRF4 Toggle-Switch Controls Tolerogenic and Immunogenic Transcriptional Programming in Human Langerhans Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
James Davies ◽  
Andres F. Vallejo ◽  
Sofia Sirvent ◽  
Gemma Porter ◽  
Kalum Clayton ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Networks ◽  
Langerhans Cells ◽  
Regulatory Networks ◽  
Mechanistic Explanation ◽  
Molecular Switches ◽  
Tnf Alpha ◽  
Toggle Switch ◽  
Gene Regulatory ◽  
Combinatorial Interactions

Langerhans cells (LCs) reside in the epidermis as a dense network of immune system sentinels, coordinating both immunogenic and tolerogenic immune responses. To determine molecular switches directing induction of LC immune activation, we performed mathematical modelling of gene regulatory networks identified by single cell RNA sequencing of LCs exposed to TNF-alpha, a key pro-inflammatory signal produced by the skin. Our approach delineated three programmes of LC phenotypic activation (immunogenic, tolerogenic or ambivalent), and confirmed that TNF-alpha enhanced LC immunogenic programming. Through regulon analysis followed by mutual information modelling, we identified IRF1 as the key transcription factor for the regulation of immunogenicity in LCs. Application of a mathematical toggle switch model, coupling IRF1 with tolerance-inducing transcription factors, determined the key set of transcription factors regulating the switch between tolerance and immunogenicity, and correctly predicted LC behaviour in LCs derived from different body sites. Our findings provide a mechanistic explanation of how combinatorial interactions between different transcription factors can coordinate specific transcriptional programmes in human LCs, interpreting the microenvironmental context of the local tissue microenvironments.

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