scholarly journals A gene regulatory motif that generates oscillatory or multiway switch outputs

2013 ◽  
Vol 10 (79) ◽  
pp. 20120826 ◽  
Author(s):  
Jasmina Panovska-Griffiths ◽  
Karen M. Page ◽  
James Briscoe
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Spatial Organization ◽  
Formation Mechanisms ◽  
Regulatory Interactions ◽  
Qualitative Dynamics ◽  
Gene Regulatory ◽  
Oscillatory Mechanisms ◽  
Parameter Values ◽  
Natural Way

The pattern of gene expression in a developing tissue determines the spatial organization of cell type generation. We previously defined regulatory interactions between a set of transcription factors that specify the pattern of gene expression in progenitors of different neuronal subtypes of the vertebrate neural tube. These transcription factors form a circuit that acts as a multistate switch, patterning the tissue in response to a gradient of Sonic Hedgehog. Here, by simplifying aspects of the regulatory interactions, we found that the topology of the circuit allows either switch-like or oscillatory behaviour depending on parameter values. The qualitative dynamics appear to be controlled by a simpler sub-circuit, which we term the AC–DC motif. We argue that its topology provides a natural way to implement a multistate gene expression switch and we show that the circuit is readily extendable to produce more distinct stripes of gene expression. Our analysis also suggests that AC–DC motifs could be deployed in tissues patterned by oscillatory mechanisms, thus blurring the distinction between pattern-formation mechanisms relying on temporal oscillations or graded signals. Furthermore, during evolution, mechanisms of gradient interpretation might have arisen from oscillatory circuits, or vice versa.

Combinatorial control of the bradykinin B2 receptor promoter by p53, CREB, KLF-4, and CBP: implications for terminal nephron differentiation

2005 ◽  
Vol 288 (5) ◽  
pp. F899-F909 ◽  
Author(s):  
Zubaida Saifudeen ◽  
Susana Dipp ◽  
Hao Fan ◽  
Samir S. El-Dahr
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Dna Binding ◽  
Spatial Organization ◽  
Kidney Development ◽  
Collecting Duct ◽  
Proximal Promoter ◽  
Bradykinin B2 Receptor ◽  
Nephron Differentiation ◽  
Terminal Nephron

Despite a wealth of knowledge regarding the early steps of epithelial differentiation, little is known about the mechanisms responsible for terminal nephron differentiation. The bradykinin B2 receptor (B2R) regulates renal function and integrity, and its expression is induced during terminal nephron differentiation. This study investigates the transcriptional regulation of the B2R during kidney development. The rat B2R 5′-flanking region has a highly conserved cis-acting enhancer in the proximal promoter consisting of contiguous binding sites for the transcription factors cAMP response element binding protein (CREB), p53, and Krüppel-like factor (KLF-4). The B2R enhancer drives reporter gene expression in inner medullary collecting duct-3 cells but is considerably weaker in other cell types. Site-directed mutagenesis and expression of dominant negative mutants demonstrated the requirement of CREB DNA binding and Ser-133 phosphorylation for optimal enhancer function. Moreover, helical phasing experiments showed that disruption of the spatial organization of the enhancer inhibits B2R promoter activity. Several lines of evidence indicate that cooperative interactions among the three transcription factors occur in vivo during terminal nephron differentiation: 1) CREB, p53, and KLF-4 are coexpressed in B2R-positive differentiating cells; 2) the maturational expression of B2R correlates with CREB/p53/KLF-4 DNA-binding activity; 3) assembly of CREB, p53, and KLF-4 on chromatin at the endogenous B2R promoter is developmentally regulated and is accompanied by CBP recruitment and histone hyperacetylation; and 4) CREB and p53 occupancy of the B2R enhancer is cooperative. These results demonstrate that combinatorial interactions among the transcription factors, CREB, p53, and KLF-4, and the coactivator CBP, may be critical for the regulation of B2R gene expression during terminal nephron differentiation.

scholarly journals Odd-paired controls frequency doubling in Drosophila segmentation by altering the pair-rule gene regulatory network

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Erik Clark ◽  
Michael Akam
Keyword(s):  
Gene Expression ◽  
Gene Regulatory Network ◽  
Regulatory Network ◽  
Frequency Doubling ◽  
Drosophila Embryo ◽  
Anteroposterior Patterning ◽  
Regulatory Interactions ◽  
Pair Rule Gene ◽  
Gene Regulatory ◽  
Pair Rule

The Drosophila embryo transiently exhibits a double-segment periodicity, defined by the expression of seven 'pair-rule' genes, each in a pattern of seven stripes. At gastrulation, interactions between the pair-rule genes lead to frequency doubling and the patterning of 14 parasegment boundaries. In contrast to earlier stages of Drosophila anteroposterior patterning, this transition is not well understood. By carefully analysing the spatiotemporal dynamics of pair-rule gene expression, we demonstrate that frequency-doubling is precipitated by multiple coordinated changes to the network of regulatory interactions between the pair-rule genes. We identify the broadly expressed but temporally patterned transcription factor, Odd-paired (Opa/Zic), as the cause of these changes, and show that the patterning of the even-numbered parasegment boundaries relies on Opa-dependent regulatory interactions. Our findings indicate that the pair-rule gene regulatory network has a temporally modulated topology, permitting the pair-rule genes to play stage-specific patterning roles.

scholarly journals OnTAD: hierarchical domain structure reveals the divergence of activity among TADs and boundaries

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Lin An ◽  
Tao Yang ◽  
Jiahao Yang ◽  
Johannes Nuebler ◽  
Guanjue Xiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Domain Structure ◽  
High Frequency ◽  
Spatial Organization ◽  
Structural Units ◽  
Regulatory Interactions ◽  
Link Type ◽  
Topologically Associating Domains

AbstractThe spatial organization of chromatin in the nucleus has been implicated in regulating gene expression. Maps of high-frequency interactions between different segments of chromatin have revealed topologically associating domains (TADs), within which most of the regulatory interactions are thought to occur. TADs are not homogeneous structural units but appear to be organized into a hierarchy. We present OnTAD, an optimized nested TAD caller from Hi-C data, to identify hierarchical TADs. OnTAD reveals new biological insights into the role of different TAD levels, boundary usage in gene regulation, the loop extrusion model, and compartmental domains. OnTAD is available at https://github.com/anlin00007/OnTAD.

scholarly journals Identifying genetic modulators of the connectivity between transcription factors and their transcriptional targets

2016 ◽  
Vol 113 (13) ◽  
pp. E1835-E1843 ◽  
Author(s):  
Mina Fazlollahi ◽  
Ivor Muroff ◽  
Eunjee Lee ◽  
Helen C. Causton ◽  
Harmen J. Bussemaker
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Target Genes ◽  
Regulation Of Gene Expression ◽  
Nonsynonymous Mutation ◽  
Gene Regulatory ◽  
Genetic Modulators

Regulation of gene expression by transcription factors (TFs) is highly dependent on genetic background and interactions with cofactors. Identifying specific context factors is a major challenge that requires new approaches. Here we show that exploiting natural variation is a potent strategy for probing functional interactions within gene regulatory networks. We developed an algorithm to identify genetic polymorphisms that modulate the regulatory connectivity between specific transcription factors and their target genes in vivo. As a proof of principle, we mapped connectivity quantitative trait loci (cQTLs) using parallel genotype and gene expression data for segregants from a cross between two strains of the yeast Saccharomyces cerevisiae. We identified a nonsynonymous mutation in the DIG2 gene as a cQTL for the transcription factor Ste12p and confirmed this prediction empirically. We also identified three polymorphisms in TAF13 as putative modulators of regulation by Gcn4p. Our method has potential for revealing how genetic differences among individuals influence gene regulatory networks in any organism for which gene expression and genotype data are available along with information on binding preferences for transcription factors.

scholarly journals What functional genomics has taught us about transcriptional regulation in malaria parasites

2019 ◽  
Vol 18 (5) ◽  
pp. 290-301 ◽  
Author(s):  
Christa G Toenhake ◽  
Richárd Bártfai
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Life Cycle ◽  
Functional Genomics ◽  
Expression Patterns ◽  
Regulatory Elements ◽  
Complex Life Cycle ◽  
Malaria Parasites ◽  
Gene Regulatory

Abstract Malaria parasites are characterized by a complex life cycle that is accompanied by dynamic gene expression patterns. The factors and mechanisms that regulate gene expression in these parasites have been searched for even before the advent of next generation sequencing technologies. Functional genomics approaches have substantially boosted this area of research and have yielded significant insights into the interplay between epigenetic, transcriptional and post-transcriptional mechanisms. Recently, considerable progress has been made in identifying sequence-specific transcription factors and DNA-encoded regulatory elements. Here, we review the insights obtained from these efforts including the characterization of core promoters, the involvement of sequence-specific transcription factors in life cycle progression and the mapping of gene regulatory elements. Furthermore, we discuss recent developments in the field of functional genomics and how they might contribute to further characterization of this complex gene regulatory network.

scholarly journals Oncogenic Notch promotes long-range regulatory interactions within hyperconnected 3D cliques

2019 ◽  
Author(s):  
Jelena Petrovic ◽  
Yeqiao Zhou ◽  
Maria Fasolino ◽  
Naomi Goldman ◽  
Gregory W. Schwartz ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Long Range ◽  
Spatial Organization ◽  
Target Genes ◽  
Large Fraction ◽  
B Cell Lymphoma ◽  
3 Dimensional ◽  
Regulatory Interactions ◽  
Genome Wide ◽  
Target Promoters

AbstractChromatin loops enable transcription factor-bound distal enhancers to interact with their target promoters to regulate transcriptional programs. Although developmental transcription factors, such as active forms of Notch, can directly stimulate transcription by activating enhancers, the effect of their oncogenic subversion on the 3-dimensional (3D) organization of the cancer genome is largely undetermined. By mapping chromatin looping genome-wide in Notch-dependent triple-negative breast cancer and B-cell lymphoma, we show that far beyond the well-characterized role of Notch as an activator of distal enhancers, Notch regulates its direct target genes through establishing new long-range regulatory interactions. Moreover, a large fraction of Notch-promoted regulatory loops forms highly interacting enhancer and promoter spatial clusters, termed “3D cliques”. Loss-and gain-of-function experiments show that Notch preferentially targets hyperconnected 3D cliques that regulate the expression of crucial proto-oncogenes. Our observations suggest that oncogenic hijacking of developmental transcription factors can dysregulate transcription through widespread effects on the spatial organization of cancer genomes.

scholarly journals Intranuclear trafficking of transcription factors: implications for biological control

2000 ◽  
Vol 113 (14) ◽  
pp. 2527-2533 ◽  
Author(s):  
G.S. Stein ◽  
A.J. van Wijnen ◽  
J.L. Stein ◽  
J.B. Lian ◽  
M. Montecino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Spatial Organization ◽  
Three Dimensional ◽  
Myelogenous Leukemia ◽  
Regulatory Factors ◽  
Acute Myelogenous ◽  
Gene Transcripts ◽  
Targeting Signals ◽  
Discrete Domains

The subnuclear organization of nucleic acids and cognate regulatory factors suggests that there are functional interrelationships between nuclear structure and gene expression. Nuclear proteins that are localized in discrete domains within the nucleus include the leukemia-associated acute myelogenous leukemia (AML) and promyelocytic leukemia (PML) factors, the SC-35 RNA-processing factors, nucleolar proteins and components of both transcriptional and DNA replication complexes. Mechanisms that control the spatial distribution of transcription factors within the three-dimensional context of the nucleus may involve the sorting of regulatory information, as well as contribute to the assembly and activity of sites that support gene expression. Molecular, cellular, genetic and biochemical approaches have identified distinct protein segments, termed intranuclear-targeting signals, that are responsible for directing regulatory factors to specific subnuclear sites. Gene rearrangements that remove or alter intranuclear-targeting signals are prevalent in leukemias and have been linked to altered localization of regulatory factors within the nucleus. These modifications in the intranuclear targeting of transcription factors might abrogate fidelity of gene expression in tumor cells by influencing the spatial organization and/or assembly of machineries involved in the synthesis and processing of gene transcripts.

scholarly journals Identifying the combinatorial control of signal-dependent transcription factors

2021 ◽  
Vol 17 (6) ◽  
pp. e1009095
Author(s):  
Ning Wang ◽  
Diane Lefaudeux ◽  
Anup Mazumder ◽  
Jingyi Jessica Li ◽  
Alexander Hoffmann
Keyword(s):  
Gene Expression ◽  
Experimental Data ◽  
Transcription Factors ◽  
Target Genes ◽  
Error Model ◽  
Modeling Framework ◽  
Response Gene ◽  
Stimulus Response ◽  
Computational Workflow ◽  
Gene Regulatory

The effectiveness of immune responses depends on the precision of stimulus-responsive gene expression programs. Cells specify which genes to express by activating stimulus-specific combinations of stimulus-induced transcription factors (TFs). Their activities are decoded by a gene regulatory strategy (GRS) associated with each response gene. Here, we examined whether the GRSs of target genes may be inferred from stimulus-response (input-output) datasets, which remains an unresolved model-identifiability challenge. We developed a mechanistic modeling framework and computational workflow to determine the identifiability of all possible combinations of synergistic (AND) or non-synergistic (OR) GRSs involving three transcription factors. Considering different sets of perturbations for stimulus-response studies, we found that two thirds of GRSs are easily distinguishable but that substantially more quantitative data is required to distinguish the remaining third. To enhance the accuracy of the inference with timecourse experimental data, we developed an advanced error model that avoids error overestimates by distinguishing between value and temporal error. Incorporating this error model into a Bayesian framework, we show that GRS models can be identified for individual genes by considering multiple datasets. Our analysis rationalizes the allocation of experimental resources by identifying most informative TF stimulation conditions. Applying this computational workflow to experimental data of immune response genes in macrophages, we found that a much greater fraction of genes are combinatorially controlled than previously reported by considering compensation among transcription factors. Specifically, we revealed that a group of known NFκB target genes may also be regulated by IRF3, which is supported by chromatin immuno-precipitation analysis. Our study provides a computational workflow for designing and interpreting stimulus-response gene expression studies to identify underlying gene regulatory strategies and further a mechanistic understanding.

scholarly journals TALE factors use two distinct functional modes to control an essential zebrafish gene expression program

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Franck Ladam ◽  
William Stanney ◽  
Ian J Donaldson ◽  
Ozge Yildiz ◽  
Nicoletta Bobola ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Regulatory Network ◽  
Hox Proteins ◽  
Oncogenic Potential ◽  
Dna Motifs ◽  
Protein Partners ◽  
Gene Regulatory ◽  
Expression Program ◽  
Functional Mode

TALE factors are broadly expressed embryonically and known to function in complexes with transcription factors (TFs) like Hox proteins at gastrula/segmentation stages, but it is unclear if such generally expressed factors act by the same mechanism throughout embryogenesis. We identify a TALE-dependent gene regulatory network (GRN) required for anterior development and detect TALE occupancy associated with this GRN throughout embryogenesis. At blastula stages, we uncover a novel functional mode for TALE factors, where they occupy genomic DECA motifs with nearby NF-Y sites. We demonstrate that TALE and NF-Y form complexes and regulate chromatin state at genes of this GRN. At segmentation stages, GRN-associated TALE occupancy expands to include HEXA motifs near PBX:HOX sites. Hence, TALE factors control a key GRN, but utilize distinct DNA motifs and protein partners at different stages – a strategy that may also explain their oncogenic potential and may be employed by other broadly expressed TFs.

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