Stochastic resonance induced by a multiplicative periodic signal in the gene transcriptional regulatory system with correlated noises

This paper investigates the stochastic resonance （SR） induced by a multiplicative periodic signal in the gene transcriptional regulatory system with correlated noises. The expression of the signal-to-noise ratio （SNR） is derived. The results indicate that the existence of a maximum in SNR vs. the additive noise intensity α the multiplicative noise intensity D and the cross-correlated noise intensity λ is the identifying characteristic of the SR phenomenon and there is a critical phenomenon in the SNR as a function of λ, i.e., for the case of smaller values of noise intensity （α or D）, the SNR decreases as λ increases; however, for the case of larger values of noise intensity （α or D）, the SNR increases as λ increases.

Stochastic resonance in the gene transcriptional regulatory system subjected to noises

We have investigated in the adiabatic limit the phenomenon of stochastic resonance in the gene transcriptional regulatory system subjected to an additive noise, a multiplicative noise, and a weakly periodic signal. Using the general two-state approach for the asymmetry system, the analytic expression of signal-to-noise ratio is obtained. The effects of the additive noise intensity a, the multiplicative noise intensity D and the amplitude of input periodic signal A on the signal-to-noise ratio are analysed by numerical calculation. It is found that the existence of a maximum in the RSNR a and RSNR D plots is the identifying characteristic of the stochastic resonance phenomenon in the weakened noise intensity region. The stochastic resonance phenomena are restrained with increasing a and D, and enhanced with increasing A.

Hypothalamic-Pituitary-Gonadal(HPG)Axis and Transcriptional Regulatory Elements Regulate piwil2 Gene Expression During Gametogenesis and Gonadal Development in Japanese Flounder(Paralichthys olivaceus)

The P-element induced wimpy testis(Piwi)proteins,which are associated with PIWI-interacting RNAs(piRNAs),play important roles in meiosis,germ cell division,and germline maintenance.In this study,we identified and characterized the Paralichthys olivaceus piwil2 gene,a constituent factor of the piRNA pathways involved in the biogenesis of reproductive development.The biological analysis indicated that piwil2,which contains PAZ and PIWI domains,was highly conserved between teleosts and tetrapods.The piwil2 distribution profile in different tissues confirmed a sexually dimorphic expression pattern,with a higher expression level in testis.In situ hybridization demonstrated that piwil2 was expressed in the oogonia and oocytes of the ovaries as well as in the Sertoli cells and spermatocytes of the testes.Gene piwil2 showed a maternally inherited expression pattern during embryonic development,and was highly expressed during the early embryonic development.Different luciferase reporters were constructed to determine the transcriptional regulatory mechanisms of piwil2.The piwil2 core promoter region was located at−360 bp to−60 bp.Furthermore,some representative sex hormones,including human chorionic gonadotropin,17α-methyltestosterone,and estradiol-17βhad distinct regulatory effects on piwil2.In a summery,these results indicate that piwil2,regulated by sex hormones and transcriptional elements,has vital functions in the reproductive cycle and gonadal development.

Nonchaoticity of Ordinary Differential Equations Describing Autonomous Transcriptional Regulatory Circuits

Gene transcriptional regulation （TR） processes are often described by coupled nonlinear ordinary differential equations （ODEs）. When the dimension of TR circuits is high （e.g. n≥3） the motions of the corresponding ODEs may, very probably, show self-sustained oscillations and chaos. On the other hand, chaoticity may be harmful for the normal biological functions of TR processes. In this letter we numerically study the dynamics of 3-gene TR ODEs in great detail, and investigate many 4-, 5-, and lO-gene TR systems by randomly choosing figures and parameters in the conventionally accepted ranges. And we find that oscillations are very seldom and no chaotic motion is observed, even if the dimension of systems is sufficiently high （n≥3）. It is argued that the observation of nonchaoticity of these ODEs agrees with normal functions of actual TR processes.

The abscisic acid-responsive transcriptional regulatory module CsERF110-CsERF53 orchestrates citrus fruit coloration

Carotenoid biosynthesis is closely associated with abscisic acid(ABA)during the ripening process of non-climacteric fruits,but the regulatory mechanism that links ABA signaling to carotenoid metabolism remains largely unclear.Here,we identified two master regulators of ABA-mediated citrus fruit coloration,CsERF110 and CsERF53,which activate the expression of carotenoid metabolism genes(CsGGPPS,CsPSY,CsPDS,CsCRTISO,CsLCYB2,CsLCYE,CsHYD,CsZEP,and CsNCED2)to facilitate carotenoid accumulation.Further investigations showed that CsERF110 not only activates the expression of CsERF53 by binding to its promoter but also interacts with CsERF53 to form the transcriptional regulatory module CsERF110-CsERF53.We also discovered a positive feedback regulatory loop between the ABA signal and carotenoid metabolism regulated by the transcriptional regulatory module CsERF110-CsERF53.Our results reveal that the CsERF110-CsERF53 module responds to ABA signaling,thereby orchestrating citrus fruit coloration.Considering the importance of carotenoid content for citrus and many other carotenoid-rich crops,the revelation of molecular mechanisms that underlie ABA-mediated carotenoid biosynthesis in plants will facilitate the development of transgenic/gene-editing approaches,further contributing to improving the quality of citrus and other carotenoid-rich crops.

Transcriptional Regulatory Networks Activated by PI3K and ERK Transduced Growth Signals in Human Glioblastoma Cells

Determining how cells regulate their transcriptional response toextracellular signals is key to the understanding of complex eukaryotic systems. This study wasinitiated with the goals of furthering the study of mammalian transcriptional regulation andanalyzing the relative benefits of related computational methodologies. One dataset available forsuch an analysis involved gene expression profiling of the early growth factor response to plateletderived growth factor (PDGF) in a human glioblastoma cell line; this study differentiated geneswhose expression was regulated by signaling through the phosphoinositide-3-kinase (PI3K) versus theextracellular-signal regulated kinase (ERK) pathways. We have compared the inferred transcriptionfactors from this previous study with additional predictions of regulatory transcription factorsusing two alternative promoter sequence analysis techniques. This comparative analysis, in which thealgorithms predict overlapping, although not identical, sets of factors, argues for meticulousbenchmarking of promoter sequence analysis methods to determine the positive and negative attributesthat contribute to their varying results. Finally, we inferred transcriptional regulatory networksderiving from various signaling pathways using the CARRIE program suite. These networks not onlyincluded previously described transcriptional features of the response to growth signals, but alsopredicted new regulatory features for the propagation and modulation of the growth signal.

The future of genome-scale modeling of yeast through integration of a transcriptional regulatory network

Metabolism is regulated at multiple levels in response to the changes of internal or external conditions. Transcriptional regulation plays an important role in regulating many metabolic reactions by altering the concentrations of metabolic enzymes. Thus, integration of the transcriptional regulatory information is necessary to improve the accuracy and predictive ability of metabolic models. Here we review the strategies for the reconstruction of a transcriptional regulatory network （TRN） for yeast and the integration of such a reconstruction into a flux balance analysis-based metabolic model. While many large-scale TRN reconstructions have been reported for yeast, these reconstructions still need to be improved regarding the functionality and dynamic property of the regulatory interactions. In addition, mathematical modeling approaches need to be further developed to efficiently integrate transcriptional regulatory interactions to genome-scale metabolic models in a quantitative manner.

Expression analysis of the R2R3-MYB gene family in upland cotton and functional study of GhMYB3D5 in regulating Verticillium wilt resistance

Improving plant resistance to Verticillium wilt(VW),which causes massive losses in Gossypium hirsutum,is a global challenge.Crop plants need to efficiently allocate their limited energy resources to maintain a balance between growth and defense.However,few transcriptional regulators specifically respond to Verticillium dahliae and the underlying mechanism has not been identified in cotton.In this study,we found that the that expression of most R2R3-MYB members in cotton is significantly changed by V.dahliae infection relative to the other MYB types.One novel R2R3-MYB transcription factor(TF)that specifically responds to V.dahliae,GhMYB3D5,was identified.GhMYB3D5 was not expressed in 15 cotton tissues under normal conditions,but it was dramatically induced by V.dahliae stress.We functionally characterized its positive role and underlying mechanism in VW resistance.Upon V.dahliae infection,the up-regulated GhMYB3D5 bound to the GhADH1 promoter and activated GhADH1expression.In addition,GhMYB3D5 physically interacted with GhADH1 and further enhanced the transcriptional activation of GhADH1.Consequently,the transcriptional regulatory module GhMYB3D5-GhADH1 then promoted lignin accumulation by improving the transcriptional levels of genes related to lignin biosynthesis(GhPAL,GhC4H,Gh4CL,and GhPOD/GhLAC)in cotton,thereby enhancing cotton VW resistance.Our results demonstrated that the GhMYB3D5 promotes defense-induced lignin accumulation,which can be regarded as an effective way to orchestrate plant immunity and growth.

Core transcriptional signatures of phase change in the migratory locust

Phenotypic plasticity plays fundamental roles in successful adaptation of animals in response to environmental variations.Here,to reveal the transcriptome reprogramming in locust phase change,a typical phenotypic plasticity,we conducted a comprehensive analysis of multiple phase-related transcriptomic datasets of the migratory locust.We defined PhaseCore genes according to their contribution to phase differentiation by the adjustment for confounding principal components analysis algorithm(AC-PCA).Compared with other genes,PhaseCore genes predicted phase status with over 87.5%accuracy and displayed more unique gene attributes including the faster evolution rate,higher CpG content and higher specific expression level.Then,we identified 20 transcription factors(TFs)named PhaseCoreTF genes that are associated with the regulation of PhaseCore genes.Finally,we experimentally verified the regulatory roles of three representative TFs(Hr4,Hr46,and grh)in phase change by RNAi.Our findings revealed that core transcriptional signatures are involved in the global regulation of locust phase changes,suggesting a potential common mechanism underlying phenotypic plasticity in insects.The expression and network data are accessible in an online resource called LocustMine(http://www.locustmine.org:8080/locustmine).

A PtrLBD39-mediated transcriptional network regulates tension wood formation in Populus trichocarpa

Tension wood(TW)is a specialized xylem tissue formed in angiosperm trees under gravitational stimulus or mechanical stresses(e.g.,bending).The genetic regulation that underlies this important mechanism remains poorly understood.Here,we used laser capture microdissection of stem xylem cells coupled with full transcriptome RNA-sequencing to analyze TW formation in Populus trichocarpa.After tree bending,PtrLBD39 was the most significantly induced transcription factor gene;it has a phylogenetically paired homolog,PtrLBD22.CRISPR-based knockout of PtrLBD39/22 severely inhibited TW formation,reducing cellulose and increasing lignin content.Transcriptomic analyses of CRISPR-based PtrLBD39/22 double mutants showed that these two genes regulate a set of TW-related genes.Chromatin immunoprecipitation sequencing(ChIP-seq)was used to identify direct targets of PtrLBD39.We integrated transcriptomic analyses and ChIP-seq assays to construct a transcriptional regulatory network(TRN)mediated by PtrLBD39.In this TRN,PtrLBD39 directly regulates 26 novel TW-responsive transcription factor genes.Our work suggests that PtrLBD39 and PtrLBD22 specifically control TW formation by mediating a TW-specific TRN in Populus.

Single-cell analysis of transcription factor regulatory networks reveals molecular basis for subtype-specific dysregulation in acute myeloid leukemia

Highly heterogeneous acute myeloid leukemia(AML)exhibits dysregulated transcriptional programs.Transcription factor(TF)regulatory networks underlying AML subtypes have not been elucidated at single-cell resolution.Here,we comprehensively mapped malignancy-related TFs activated in different AML subtypes by analyzing single-cell RNA sequencing data from AMLs and healthy donors.We first identified six modules of regulatory networks which were prevalently dysregulated in all AML patients.AML subtypes featured with different malignant cellular composition possessed subtype-specific regulatory TFs associated with differentiation suppression or immune modulation.At last,we validated that ERF was crucial for the development of hematopoietic stem/progenitor cells by performing loss-and gain-of-function experiments in zebrafish embryos.Collectively,our work thoroughly documents an abnormal spectrum of transcriptional regulatory networks in AML and reveals subtype-specific dysregulation basis,which provides a prospective view to AML pathogenesis and potential targets for both diagnosis and therapy.

Effects of Shen-Fu Injection (参附注射液) on Apoptosis of Regulatory T Lymphocytes in Spleen during Post-Resuscitation Immune Dysfunction in A Porcine Model of Cardiac Arrest

Objective： To investigate whether Shen-Fu Injection（参附注射液, SFI） reduces post-resuscitation immune dysfunction in a porcine model of cardiac arrest by modulating apoptosis of regulatory T lymphocytes（Treg） in the spleen. Methods： After 8-min untreated ventricular fibrillation and 2-min basic life support, 24 pigs were divided into 3 groups with a random number table, i.e. SFI group, epinephrine（EP） group, and saline（SA） group（8 in each group）, which received central venous injection of SFI（1.0 m L/kg）, EP（0.02 mg/kg） and SA, respectively. The same procedure without CA initiation was achieved in the sham-operated（sham） group（n=6）. After successful return of spontaneous circulation（ROSC）, apoptosis rate of splenic Treg was detected by flow cytometry; and the m RNA expression of forkhead/winged helix transcription factor（Foxp3） of splenic Treg was detected by real time-polymerase chain reaction; and the levels of interleukin-4（IL-4） and interferon-γ（IFN-γ） in porcine splenic Treg were detected by using enzyme-linked immunosorbent assay（ELISA）. Results： Compared with the sham group, the apoptosis rate of Treg was significantly decreased, and the levels of Foxp3 m RNA expression, IFN-γ, IL-4 and IFN-γ/IL-4 were increased in the SA group（P〈0.05 or P〈0.01）. Compared with the EP and SA groups, SFI treatment increased the apoptosis rate of Treg and reduced the levels of Foxp3 m RNA expression, IFN-γ and IFN-γ/IL-4（P〈0.05）. Conclusions： SFI has significant effects in attenuating post-resuscitation immune dysfunction by modulating apoptosis of Treg in the spleen.

Transcription factor EHF interacting with coactivator AJUBA aggravates malignancy and acts as a therapeutic target for gastroesophageal adenocarcinoma

Transcriptional dysregulation of genes is a hallmark of tumors and can serve as targets for cancer drug development.However,it is extremely challenging to develop small-molecule inhibitors to target abnormally expressed transcription factors(TFs)except for the nuclear receptor family of TFs.Little is known about the interaction between TFs and transcription cofactors in gastroesophageal adenocarcinoma(GEA)or the therapeutic effects of targeting TF and transcription cofactor complexes.In this study,we found that ETS homologous factor(EHF)expression is promoted by a core transcriptional regulatory circuitry(CRC),specifically ELF3-KLF5-GATA6,and interference with its expression suppressed the malignant biological behavior of GEA cells.Importantly,we identified Ajuba LIM protein(AJUBA)as a new coactivator of EHF that cooperatively orchestrates transcriptional network activity in GEA.Furthermore,we identified KRAS signaling as a common pathway downstream of EHF and AJUBA.Applicably,dual targeting of EHF and AJUBA by lipid nanoparticles cooperatively attenuated the malignant biological behaviors of GEA in vitro and in vivo.In conclusion,EHF is upregulated by the CRC and promotes GEA malignancy by interacting with AJUBA through the KRAS pathway.Targeting of both EHF and its coactivator AJUBA through lipid nanoparticles is a novel potential therapeutic strategy.

Functional predictability of universal gene circuits in diverse microbial hosts

Although the principles of synthetic biology were initially established in model bacteria,microbial producers,extremophiles and gut microbes have now emerged as valuable prokaryotic chassis for biological engineering.Extending the host range in which designed circuits can function reliably and predictably presents a major challenge for the concept of synthetic biology to materialize.In this work,we systematically characterized the cross-species universality of two transcriptional regulatory modules—the T7 RNA polymerase activator module and the repressors module—in three non-model microbes.We found striking linear relationships in circuit activities among different organisms for both modules.Parametrized model fitting revealed host non-specific parameters defining the universality of both modules.Lastly,a genetic NOT gate and a band-pass filter circuit were constructed from these modules and tested in non-model organisms.Combined models employing host non-specific parameters were successful in quantitatively predicting circuit behaviors,underscoring the potential of universal biological parts and predictive modeling in synthetic bioengineering.

Maize endosperm development

Recent breakthroughs in transcriptome analysis and gene characterization have provided valuable resources and information about the maize endosperm developmental program.The high temporal-resolution transcriptome analysis has yielded unprecedented access to information about the genetic control of seed development.Detailed spatial transcriptome analysis using laser-capture microdissection has revealed the expression patterns of specific populations of genes in the four major endosperm compartments:the basal endosperm transfer layer(BETL),aleurone layer(AL),starchy endosperm(SE),and embryo-surrounding region(ESR).Although the overall picture of the transcriptional regulatory network of endosperm development remains fragmentary,there have been some exciting advances,such as the identification of OPAQUE11(O11)as a central hub of the maize endosperm regulatory network connecting endosperm development,nutrient metabolism,and stress responses,and the discovery that the endosperm adjacent to scutellum(EAS)serves as a dynamic interface for endosperm-embryo crosstalk.In addition,several genes that function in BETL development,AL differentiation,and the endosperm cell cycle have been identified,such as ZmSWEET4c,Thk1,and Dek15,respectively.Here,we focus on current advances in understanding the molecular factors involved in BETL,AL,SE,ESR,and EAS development,including the specific transcriptional regulatory networks that function in each compartment during endosperm development.

Codimensional matrix pairing perspective of BYY harmony learning:hierarchy of bilinear systems,joint decomposition of data-covariance,and applications of network biology

One paper in a preceding issue of this journal has introduced the Bayesian Ying-Yang(BYY)harmony learning from a perspective of problem solving,parameter learning,and model selection.In a complementary role,the paper provides further insights from another perspective that a co-dimensional matrix pair(shortly co-dim matrix pair)forms a building unit and a hierarchy of such building units sets up the BYY system.The BYY harmony learning is re-examined via exploring the nature of a co-dim matrix pair,which leads to improved learning performance with refined model selection criteria and a modified mechanism that coordinates automatic model selection and sparse learning.Besides updating typical algorithms of factor analysis(FA),binary FA(BFA),binary matrix factorization(BMF),and nonnegative matrix factorization(NMF)to share such a mechanism,we are also led to(a)a new parametrization that embeds a de-noise nature to Gaussian mixture and local FA(LFA);(b)an alternative formulation of graph Laplacian based linear manifold learning;(c)a codecomposition of data and covariance for learning regularization and data integration;and(d)a co-dim matrix pair based generalization of temporal FA and state space model.Moreover,with help of a co-dim matrix pair in Hadamard product,we are led to a semi-supervised formation for regression analysis and a semi-blind learning formation for temporal FA and state space model.Furthermore,we address that these advances provide with new tools for network biology studies,including learning transcriptional regulatory,Protein-Protein Interaction network alignment,and network integration.

From Decision to Commitment： The Molecular Memory of Flowering

During the floral transition the shoot apical meristem changes its identity from a vegetative to an inflorescence state. This change in identity can be promoted by external signals, such as inductive photoperiod conditions or vernalization, and is accompanied by changes in expression of key developmental genes. The change in meristem identity is usually not reversible, even if the inductive signal occurs only transiently. This implies that at least some of the key genes must possess an intrinsic memory of the newly acquired expression state that ensures irreversibility of the process. In this review, we discuss different molecular scenarios that may underlie a molecular memory of gene expression.