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.

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.

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.

Phytochrome-regulated Gene Expression

Identification of all genes involved in the phytochrome （phy）-medieted responses of plants to their light environment is an important goal in providing an overall understanding of light-regulated growth end development. This article highlights end integrates the central findings of two recent comprehensive studies in Arabidopsis that have identified the genome-wide set of phy-reguleted genes that respond rapidly to red-light signals upon first exposure of dark-grown seedlings, and have tested the functional relevance to normal seedling photomorphogenesis of an Initial subset of these genes. The data： （a） reveal considerable complexity in the channeling of the light signals through the different phy-femily members （phyA to phyE） to responsive genes; （b） identify a diversity of transcription-factor-encoding genes as major early, if not primary, targets of phy signaling, end, therefore, as potentially important regulators in the transcriptional-network hierarchy; and （c） identify auxin-related genes as the dominant class among rapidly-regulated, hormone-related genes. However, reverse-genetic functional profiling of a selected subset of these genes reveals that only a limited fraction are necessary for optimal phy-induced seedling deetioletion.

Mapping of de novo mutations in primary biliary cholangitis to a disease-specific co-expression network underlying homeostasis and metabolism

Primary biliary cholangitis(PBC) is an autoimmune disease involving dysregulation of a broad array of homeostatic and metabolic processes. Although considerable single-nucleotide polymorphisms have been unveiled, a large fraction of risk factors remains enigmatic. Candidate genes with rare mutations that tend to confer more deleterious effects need to be identified. To help pinpoint cellular and developmental mechanisms beyond common noncoding variants, we integrate whole exome sequencing with integrative network analysis to investigate genes harboring de novo mutations. Prominent convergence has been revealed on a network of disease-specific co-expression comprised of 55 genes associated with homeostasis and metabolism. The transcription factor gene MEF2 D and the DNA repair gene PARP2 are highlighted as hub genes and identified to be up-and down-regulated, respectively, in peripheral blood data set. Enrichment analysis demonstrates that altered expression of MEF2 D and PARP2 may trigger a series of molecular and cellular processes with pivotal roles in PBC pathophysiology. Our study identifies genes with de novo mutations in PBC and suggests that a subset of genes in homeostasis and metabolism tend to act in synergy through converging on co-expression network, providing novel insights into the etiology of PBC and expanding the pool of molecular candidates for discovering clinically actionable biomarkers.

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.

Transition of primary to secondary cell wall synthesis

The construction of a secondary cell wall is an important and necessary developmental decision that sup- ports cell function and plant stature. Unlike the primary cell walls, which are initiated during cell division and develop along with the expansion of the cells, secondary cell walls are constructed after the cells have stopped growing. Hence, the transition from primary to secondary wall synthesis marks an important and distinct metabolic investment by the plant. This transition requires a coordi- nated change of a plethora of cellular processes, including hormonal, transcriptional and post-transcriptional activi- ties, metabolic flux re-distributions and enzymatic activities. In this review, we briefly summarize the hormonal and transcriptional control of the primary to secondary wall transition, and highlight important gaps in our under- standing of the metabolic framework that support the transition. Several tools that may aid in future research efforts to better understand the changes in cell wall synthesis during the trans-differentiation are also discussed.

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.