scholarly journals Reprogramming, oscillations and transdifferentiation in epigenetic landscapes

2017 ◽  
Author(s):  
Bivash Kaity ◽  
Ratan Sarkar ◽  
Buddhapriya Chakrabarti ◽  
Mithun K. Mitra
Keyword(s):  
Cell Differentiation ◽  
Regulatory Networks ◽  
Delayed Feedback ◽  
Regulatory Circuits ◽  
Undifferentiated State ◽  
Gene Regulatory ◽  
Programming Process ◽  
Gene Regulatory Circuits ◽  
Differentiation Pathways ◽  
Time Delayed Feedback

Waddington’s epigenetic landscape provides a phenomenological understanding of the cell differentiation pathways from the pluripotent to mature lineage-committed cell lines. In light of recent successes in the reverse programming process there has been significant interest in quantifying the underlying landscape picture through the mathematics of gene regulatory networks. We investigate the role of time delays arising from multistep chemical reactions and epigenetic rearrangement on the cell differentiation landscape for a realistic two-gene regulatory network, consisting of selfpromoting and mutually inhibiting genes. Our work provides the first theoretical basis of the transdifferentiation process in the presence of delays, where one differentiated cell type can transition to another directly without passing through the undifferentiated state. Additionally, the interplay of time-delayed feedback and a time dependent chemical drive leads to long-lived oscillatory states in appropriate parameter regimes. This work emphasizes the important role played by time-delayed feedback loops in gene regulatory circuits and provides a framework for the characterization of epigenetic landscapes.

scholarly journals Synthetic 5’ UTRs can either up- or down-regulate expression upon RBP binding

2017 ◽  
Author(s):  
Noa Katz ◽  
Roni Cohen ◽  
Oz Solomon ◽  
Beate Kaufmann ◽  
Orna Atar ◽  
...  
Keyword(s):  
Regulatory Networks ◽  
Cooperative Behavior ◽  
Transcriptional Level ◽  
Rna Molecules ◽  
Regulatory Modules ◽  
Regulatory Circuits ◽  
Rna Hairpins ◽  
Gene Regulatory ◽  
Gene Regulatory Circuits

SUMMARYThe construction of complex gene regulatory networks requires both inhibitory and up-regulatory modules. However, the vast majority of RNA-based regulatory “parts” are inhibitory. Using a synthetic biology approach combined with SHAPE-Seq, we explored the regulatory effect of RBP-RNA interactions in bacterial 5’-UTRs. By positioning a library of RNA hairpins upstream of a reporter gene and co-expressing them with the matching RBP, we observed a set of regulatory responses, including translational stimulation, translational repression, and cooperative behavior. Our combined approach revealed three distinct states in-vivo: in the absence of RBPs, the RNA molecules can be found either in a molten state that is amenable to translation, or a structured phase that inhibits translation. In the presence of RBPs, the RNA molecules are in a semi-structured phase with partial translational capacity. Our work provides new insight into RBP-based regulation and a blueprint for designing complete gene regulatory circuits at the post-transcriptional level.

scholarly journals A model for the spatio-temporal design of gene regulatory circuits

2019 ◽  
Author(s):  
Ruud Stoof ◽  
Alexander Wood ◽  
Ángel Goñi-Moreno
Keyword(s):  
Regulatory Networks ◽  
Bacterial Gene ◽  
Regulatory Circuits ◽  
Vital Functions ◽  
Gene Expression Dynamics ◽  
Gene Regulatory ◽  
Spatio Temporal ◽  
Gene Regulatory Circuits ◽  
Dna Components ◽  
Engineered Bacteria

AbstractThe design of increasingly complex gene regulatory networks relies upon mathematical modelling to link the gap that goes from conceptualisation to implementation. An overarching challenge is to update modelling abstractions and assumptions as new mechanistic information arises. Although models of bacterial gene regulation are often based on the assumption that the role played by intracellular physical distances between genetic elements is negligible, it has been shown that bacteria are highly ordered organisms, compartmentalizing their vital functions in both time and space. Here, we analysed the dynamical properties of regulatory interactions by explicitly modelling spatial constraints. Key to the model is the combined search by a regulator for its target promoter via 1D sliding along the chromosome and 3D diffusion through the cytoplasm. Moreover, this search was coupled to gene expression dynamics, with special attention to transcription factor-promoter interplay. As a result, promoter activity within the model depends on its physical separation from the regulator source. Simulations showed that by modulating the distance between DNA components in the chromosome, output levels changed accordingly. Finally, previous experimental results with engineered bacteria in which this distance was minimized or enlarged were successfully reproduced by the model. This suggests that the spatial specification of the circuit alone can be exploited as a design parameter to select programmable output levels.

scholarly journals Integrated Gene Regulatory Circuits: Celebrating the 50th Anniversary of the Operon Model

2011 ◽  
Vol 43 (4) ◽  
pp. 505-514 ◽  
Author(s):  
Shahragim Tajbakhsh ◽  
Giacomo Cavalli ◽  
Evelyne Richet
Keyword(s):  
50Th Anniversary ◽  
Regulatory Circuits ◽  
Gene Regulatory ◽  
Gene Regulatory Circuits

scholarly journals Reconstruction of the global neural crest gene regulatory networkin vivo

2018 ◽  
Author(s):  
Ruth M Williams ◽  
Ivan Candido-Ferreira ◽  
Emmanouela Repapi ◽  
Daria Gavriouchkina ◽  
Upeka Senanayake ◽  
...  
Keyword(s):  
Neural Crest ◽  
Regulatory Networks ◽  
Transcriptome Profiling ◽  
Integrated Approach ◽  
Precise Control ◽  
Regulatory Circuits ◽  
A Genome ◽  
Gene Regulatory ◽  
Cell Transcriptome

AbstractPrecise control of developmental processes is encoded in the genome in the form of gene regulatory networks (GRNs). Such multi-factorial systems are difficult to decode in vertebrates owing to their complex gene hierarchies and transient dynamic molecular interactions. Here we present a genome-widein vivoreconstruction of the GRN underlying development of neural crest (NC), an emblematic embryonic multipotent cell population. By coupling NC-specific epigenomic and single-cell transcriptome profiling with genome/epigenome engineeringin vivo, we identify multiple regulatory layers governing NC ontogeny, including NC-specific enhancers and super-enhancers, noveltrans-factors andcis-signatures. Assembling the NC regulome has allowed the comprehensive reverse engineering of the NC-GRN at unprecedented resolution. Furthermore, identification and dissection of divergent upstream combinatorial regulatory codes has afforded new insights into opposing gene circuits that define canonical and neural NC fates. Our integrated approach, allowing dissection of cell-type-specific regulatory circuitsin vivo, has broad implications for GRN discovery and investigation.

scholarly journals The miRNA-gene regulatory circuits in nSARS-CoV-2 and their potential correlations with pulmonary and thrombotic disorders

2020 ◽  
Author(s):  
Pankaj Khurana ◽  
Apoorv Gupta ◽  
Ragumani Sugadev ◽  
Y K Sharma ◽  
Rajeev Varshney ◽  
...  
Keyword(s):  
Drug Targets ◽  
Molecular Mechanisms ◽  
Cell Cycle Control ◽  
Mirna Gene ◽  
Protein Stabilization ◽  
Common Mechanism ◽  
The Novel ◽  
Regulatory Circuits ◽  
Gene Regulatory ◽  
Gene Regulatory Circuits

Abstract In view of the worldwide spread of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (nSARS-CoV-2) infection pandemic situation, research to repurpose drugs, identify novel drug targets, vaccine candidates, diagnostic markers etc have created a new race to curb the disease. To uncover nSARS-CoV-2-related important biological features and understanding the molecular basis of this disease, network biology and miRNA-gene regulatory motif-based approach is used. 11 antiviral human-microRNAs (miRNAs) which can potentially target SARS-CoV-2 genes were collated; their direct miRNA interactors were identified and a comprehensive nSARS-CoV-2 responsive miRNA:Transcription Factor (TF):gene coregulatory network was built. 1385 miRNA:TF:gene tripartite, Feed-Forward Loops (FFLs) were identified from the network. The network topology was mapped into the biological space and the overrepresented pathways were identified. Four regulatory circuits: hsa-mir-9-5p-EP300-PLCB4, hsa-mir-324-3p-MYC-HLA-F, hsa-mir-1827-E2F1-CTSV and hsa-mir-1277-5p-SP1-CANX are identified. These miRNA-gene regulatory circuits are found to regulate signalling pathways like virus endocytosis, viral replication, inflammatory response, pulmonary vascularization, cell cycle control, virus spike protein stabilization, antigen presentation, etc. Some novel computational evidences for understanding nSARS-CoV-2 molecular mechanisms controlled by these regulatory circuits is put forth. The novel associations of miRNAs and genes identified with this infection are open for experimental validation. Further, these regulatory circuits also suggest potential correlations/similarity in the molecular mechanisms during nSARS-CoV-2 infection and pulmonary diseases and thromboembolic disorders. A detailed molecular snapshot of TGF-β signalling pathway as the common mechanism that could play an important role in controlling common pathophysiology i.e. systemic inflammation, increased pulmonary pressure, ground glass opacities, D-dimer overexpression is also put forth.

scholarly journals Variation, Variegation and Heritable Gene Repression in S. cerevisiae

2021 ◽  
Vol 12 ◽  
Author(s):  
Kholoud Shaban ◽  
Safia Mahabub Sauty ◽  
Krassimir Yankulov
Keyword(s):  
Gene Expression ◽  
Current Knowledge ◽  
Regulatory Circuits ◽  
Epigenetic Diversity ◽  
Short And Long Term ◽  
Unstructured Proteins ◽  
Gene Regulatory ◽  
Gene Regulatory Circuits ◽  
Insight Into

Phenotypic heterogeneity provides growth advantages for a population upon changes of the environment. In S. cerevisiae, such heterogeneity has been observed as “on/off” states in the expression of individual genes in individual cells. These variations can persist for a limited or extended number of mitotic divisions. Such traits are known to be mediated by heritable chromatin structures, by the mitotic transmission of transcription factors involved in gene regulatory circuits or by the cytoplasmic partition of prions or other unstructured proteins. The significance of such epigenetic diversity is obvious, however, we have limited insight into the mechanisms that generate it. In this review, we summarize the current knowledge of epigenetically maintained heterogeneity of gene expression and point out similarities and converging points between different mechanisms. We discuss how the sharing of limiting repression or activation factors can contribute to cell-to-cell variations in gene expression and to the coordination between short- and long- term epigenetic strategies. Finally, we discuss the implications of such variations and strategies in adaptation and aging.

scholarly journals Dynamics of embryonic stem cell differentiation inferred from single-cell transcriptomics show a series of transitions through discrete cell states

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Sumin Jang ◽  
Sandeep Choubey ◽  
Leon Furchtgott ◽  
Ling-Nan Zou ◽  
Adele Doyle ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Single Cell ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Embryonic Stem ◽  
Stem Cell Differentiation ◽  
Embryonic Stem Cell Differentiation ◽  
Cell Fate Decisions ◽  
Transcriptomics Data ◽  
Gene Regulatory

The complexity of gene regulatory networks that lead multipotent cells to acquire different cell fates makes a quantitative understanding of differentiation challenging. Using a statistical framework to analyze single-cell transcriptomics data, we infer the gene expression dynamics of early mouse embryonic stem (mES) cell differentiation, uncovering discrete transitions across nine cell states. We validate the predicted transitions across discrete states using flow cytometry. Moreover, using live-cell microscopy, we show that individual cells undergo abrupt transitions from a naïve to primed pluripotent state. Using the inferred discrete cell states to build a probabilistic model for the underlying gene regulatory network, we further predict and experimentally verify that these states have unique response to perturbations, thus defining them functionally. Our study provides a framework to infer the dynamics of differentiation from single cell transcriptomics data and to build predictive models of the gene regulatory networks that drive the sequence of cell fate decisions during development.

Sign in / Sign up

Export Citation Format

Share Document