scholarly journals Framework estimation of stochastic gene activation using transcription average level

2021 ◽  
Author(s):  
Liang Chen ◽  
Genghong Lin ◽  
Feng Jiao
Keyword(s):  
Single Cell ◽  
Gene Activation ◽  
Mouse Fibroblast ◽  
Dynamic Features ◽  
Efficient Procedure ◽  
Tumor Necrosis Factor Induction ◽  
Transcription Data ◽  
Rate Limiting ◽  
Necrosis Factor ◽  
Rule Out

Gene activation is usually a non-Markovian process that has been modeled as various frameworks that consist of multiple rate-limiting steps. Understanding the exact activation framework for a gene of interest is a central problem for single-cell studies. In this paper, we focus on the dynamical data of the average transcription level M(t), which is typically neglected when deciphering gene activation. Firstly, the smooth trend lines of M(t) data present rich, visually dynamic features. Secondly, tractable analysis of M(t) allows the establishment of bijections between M(t) dynamics and system parameter regions. Because of these two clear advantages, we can rule out frameworks that fail to capture M(t) features and we can further test potential competent frameworks by fitting M(t) data. We implemented this procedure to determine an exact activation framework for a large number of mouse fibroblast genes under tumor necrosis factor induction; the cross-talk between the signaling and basal pathways is crucial to trigger the first peak of M(t), while the following damped gentle M(t) oscillation is regulated by the multi-step basal pathway. Moreover, the fitted parameters for the mouse genes tested revealed two distinct regulation scenarios for transcription dynamics. Taken together, we were able to develop an efficient procedure for using traditional M(t) data to estimate the gene activation frameworks and system parameters. This procedure, together with sophisticated single-cell transcription data, may facilitate a more accurate understanding of stochastic gene activation.

scholarly journals Direct observation of frequency modulated transcription in single cells using light activation

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Daniel R Larson ◽  
Christoph Fritzsch ◽  
Liang Sun ◽  
Xiuhau Meng ◽  
David S Lawrence ◽  
...  
Keyword(s):  
Single Cell ◽  
Single Molecule ◽  
Single Cell Analysis ◽  
Cell Model ◽  
Single Cells ◽  
Single Gene ◽  
Gene Activation ◽  
Light Activation ◽  
Dynamic Synthesis ◽  
Single Cell Model

Single-cell analysis has revealed that transcription is dynamic and stochastic, but tools are lacking that can determine the mechanism operating at a single gene. Here we utilize single-molecule observations of RNA in fixed and living cells to develop a single-cell model of steroid-receptor mediated gene activation. We determine that steroids drive mRNA synthesis by frequency modulation of transcription. This digital behavior in single cells gives rise to the well-known analog dose response across the population. To test this model, we developed a light-activation technology to turn on a single steroid-responsive gene and follow dynamic synthesis of RNA from the activated locus.

scholarly journals Single Cell Profiling of Acute Kidney Injury Reveals Novel Transcriptional Signatures, Mixed Identities and Epithelial-to-Stromal Crosstalk

2019 ◽  
Author(s):  
Valeria Rudman-Melnick ◽  
Mike Adam ◽  
Andrew Potter ◽  
Saagar M. Chokshi ◽  
Qing Ma ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Single Cell ◽  
Stromal Cells ◽  
Gene Activation ◽  
Kidney Injury ◽  
Rapid Decline ◽  
Renal Tubules ◽  
Developmental Gene ◽  
Single Cell Profiling

SummaryAcute kidney injury (AKI) is a rapid decline of renal function, with an incidence of up to 67% of intensive care unit patients. Current treatments are merely supportive, emphasizing the need for deeper understanding that could lead to improved therapies. We used single cell RNA sequencing, in situ hybridization and protein expression analyses to create comprehensive renal cell specific transcriptional profiles of multiple AKI stages. We revealed that AKI induces marked dedifferentiation, renal developmental gene activation and mixed identities in injured renal tubules. Moreover, we identified potential pathologic crosstalk between epithelial and stromal cells, and several novel genes involved in AKI. We also demonstrated the definitive effects of age on AKI outcome, and showed that renal developmental genes hold a potential as novel AKI markers. Moreover, our study provides the resource power which will aid in unraveling the molecular genetics of AKI.

scholarly journals The dynamics of gene expression in vertebrate embryogenesis at single-cell resolution

Science ◽  
2018 ◽  
Vol 360 (6392) ◽  
pp. eaar5780 ◽  
Author(s):  
James A. Briggs ◽  
Caleb Weinreb ◽  
Daniel E. Wagner ◽  
Sean Megason ◽  
Leonid Peshkin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Time Series ◽  
Single Cell ◽  
Companion Paper ◽  
Embryonic Cell ◽  
Marker Genes ◽  
Dynamic Features ◽  
Developmental Relationships ◽  
Developmental Gene Expression ◽  
Cell Transcriptome

Time series of single-cell transcriptome measurements can reveal dynamic features of cell differentiation pathways. From measurements of whole frog embryos spanning zygotic genome activation through early organogenesis, we derived a detailed catalog of cell states in vertebrate development and a map of differentiation across all lineages over time. The inferred map recapitulates most if not all developmental relationships and associates new regulators and marker genes with each cell state. We find that many embryonic cell states appear earlier than previously appreciated. We also assess conflicting models of neural crest development. Incorporating a matched time series of zebrafish development from a companion paper, we reveal conserved and divergent features of vertebrate early developmental gene expression programs.

scholarly journals Akt-Dependent Phosphorylation Specifically Regulates Cot Induction of NF-κB-Dependent Transcription

2002 ◽  
Vol 22 (16) ◽  
pp. 5962-5974 ◽  
Author(s):  
Lawrence P. Kane ◽  
Marianne N. Mollenauer ◽  
Zheng Xu ◽  
Christoph W. Turck ◽  
Arthur Weiss
Keyword(s):  
Protein Kinase ◽  
Signaling Pathways ◽  
Cellular Transformation ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Iκb Kinase ◽  
Ikk Complex ◽  
Mitogen Activated Protein ◽  
Tumor Necrosis Factor Induction ◽  
Necrosis Factor

ABSTRACT The Akt (or protein kinase B) and Cot (or Tpl-2) serine/threonine kinases are associated with cellular transformation. These kinases have also been implicated in the induction of NF-κB-dependent transcription. As a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family, Cot can also activate MAP kinase signaling pathways that target AP-1 and NFAT family transcription factors. Here we show that Akt and Cot physically associate and functionally cooperate. Akt appears to function upstream of Cot, as Akt can enhance Cot induction of NF-κB-dependent transcription, and dominant-negative Cot blocks the activation of this element by Akt. Furthermore, deletion analysis shows that binding to Akt is critical for Cot function. The regulation of NF-κB-dependent transcription by Cot requires Akt-dependent phosphorylation of serine 400 (S400), near the carboxy terminus of Cot. However, phosphorylation at this site is not required for Cot kinase activity or AP-1 induction, suggesting it specifically regulates Cot effector function at the level of the NF-κB pathway. Mutation of S400 in Cot does indeed abolish its ability to activate IκB-kinase (IKK) complexes, but paradoxically it allows for increased Cot association with the IKK complex. This mutated form of Cot also acts as a dominant negative for T-cell antigen receptor/CD28- or Akt/phorbol myristate acetate-induced NF-κB induction, while having relatively little effect on tumor necrosis factor induction of NF-κB. These findings suggest that the activation of different signaling pathways by MAP3Ks may be regulated separately and may provide evidence for how such discrimination by one member of this kinase family occurs.

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