scholarly journals Transcription Factors Targeted by miRNAs Regulating Smooth Muscle Cell Growth and Intimal Thickening after Vascular Injury

2019 ◽  
Vol 20 (21) ◽  
pp. 5445 ◽  
Author(s):  
Khachigian
Keyword(s):  
Smooth Muscle ◽  
Transcription Factors ◽  
Regulatory Networks ◽  
Coronary Intervention ◽  
Neointima Formation ◽  
Intimal Thickening ◽  
Cellular Processes ◽  
Percutaneous Coronary ◽  
Gene Regulatory ◽  
Non Coding Rnas

Neointima formation after percutaneous coronary intervention (PCI) is a manifestation of “phenotype switching” by vascular smooth muscle cells (SMC), a process that involves de-differentiation from a contractile quiescent phenotype to one that is richly synthetic. In response to injury, SMCs migrate, proliferate, down-regulate SMC-specific differentiation genes, and later, can revert to the contractile phenotype. The vascular response to injury is regulated by microRNAs (or miRNAs), small non-coding RNAs that control gene expression. Interactions between miRNAs and transcription factors impact gene regulatory networks. This article briefly reviews the roles of a range of miRNAs in molecular and cellular processes that control intimal thickening, focusing mainly on transcription factors, some of which are encoded by immediate-early genes. Examples include Egr-1, junB, KLF4, KLF5, Elk-1, Ets-1, HMGB1, Smad1, Smad3, FoxO4, SRF, Rb, Sp1 and c-Myb. Such mechanistic information could inform the development of strategies that block SMC growth, neointima formation, and potentially overcome limitations of lasting efficacy following PCI.

scholarly journals The Contribution of Autophagy and LncRNAs to MYC-Driven Gene Regulatory Networks in Cancers

2021 ◽  
Vol 22 (16) ◽  
pp. 8527
Author(s):  
Leila Jahangiri ◽  
Perla Pucci ◽  
Tala Ishola ◽  
Ricky M. Trigg ◽  
John A. Williams ◽  
...  
Keyword(s):  
Gene Networks ◽  
Regulatory Networks ◽  
Metabolic Reprogramming ◽  
Cellular Processes ◽  
Cancer Genomes ◽  
Mutual Regulation ◽  
Myc Gene ◽  
Gene Regulatory ◽  
Non Coding Rnas

MYC is a target of the Wnt signalling pathway and governs numerous cellular and developmental programmes hijacked in cancers. The amplification of MYC is a frequently occurring genetic alteration in cancer genomes, and this transcription factor is implicated in metabolic reprogramming, cell death, and angiogenesis in cancers. In this review, we analyse MYC gene networks in solid cancers. We investigate the interaction of MYC with long non-coding RNAs (lncRNAs). Furthermore, we investigate the role of MYC regulatory networks in inducing changes to cellular processes, including autophagy and mitophagy. Finally, we review the interaction and mutual regulation between MYC and lncRNAs, and autophagic processes and analyse these networks as unexplored areas of targeting and manipulation for therapeutic gain in MYC-driven malignancies.

scholarly journals Non-Coding RNAs and their Integrated Networks

2019 ◽  
Vol 16 (3) ◽  
Author(s):  
Peijing Zhang ◽  
Wenyi Wu ◽  
Qi Chen ◽  
Ming Chen
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Protein Coding ◽  
Integrated Networks ◽  
Cellular Processes ◽  
Sequencing Technologies ◽  
Different Types ◽  
Gene Regulatory ◽  
Non Coding Rnas ◽  
Eukaryotic Genomes

AbstractEukaryotic genomes are pervasively transcribed. Besides protein-coding RNAs, there are different types of non-coding RNAs that modulate complex molecular and cellular processes. RNA sequencing technologies and bioinformatics methods greatly promoted the study of ncRNAs, which revealed ncRNAs’ essential roles in diverse aspects of biological functions. As important key players in gene regulatory networks, ncRNAs work with other biomolecules, including coding and non-coding RNAs, DNAs and proteins. In this review, we discuss the distinct types of ncRNAs, including housekeeping ncRNAs and regulatory ncRNAs, their versatile functions and interactions, transcription, translation, and modification. Moreover, we summarize the integrated networks of ncRNA interactions, providing a comprehensive landscape of ncRNAs regulatory roles.

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 The PARP Inhibitor Olaparib Modulates the Transcriptional Regulatory Networks of Long Non-Coding RNAs during Vasculogenic Mimicry

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2690
Author(s):  
Mónica Fernández-Cortés ◽  
Eduardo Andrés-León ◽  
Francisco Javier Oliver
Keyword(s):  
Transcription Factors ◽  
Binding Sites ◽  
Regulatory Networks ◽  
Target Genes ◽  
Parp Inhibitor ◽  
Vasculogenic Mimicry ◽  
Transcriptome Profiling ◽  
Key Species ◽  
Non Coding Rnas ◽  
The Impact

In highly metastatic tumors, vasculogenic mimicry (VM) involves the acquisition by tumor cells of endothelial-like traits. Poly-(ADP-ribose) polymerase (PARP) inhibitors are currently used against tumors displaying BRCA1/2-dependent deficient homologous recombination, and they may have antimetastatic activity. Long non-coding RNAs (lncRNAs) are emerging as key species-specific regulators of cellular and disease processes. To evaluate the impact of olaparib treatment in the context of non-coding RNA, we have analyzed the expression of lncRNA after performing unbiased whole-transcriptome profiling of human uveal melanoma cells cultured to form VM. RNAseq revealed that the non-coding transcriptomic landscape differed between olaparib-treated and non-treated cells: olaparib significantly modulated the expression of 20 lncRNAs, 11 lncRNAs being upregulated, and 9 downregulated. We subjected the data to different bioinformatics tools and analysis in public databases. We found that copy-number variation alterations in some olaparib-modulated lncRNAs had a statistically significant correlation with alterations in some key tumor suppressor genes. Furthermore, the lncRNAs that were modulated by olaparib appeared to be regulated by common transcription factors: ETS1 had high-score binding sites in the promoters of all olaparib upregulated lncRNAs, while MZF1, RHOXF1 and NR2C2 had high-score binding sites in the promoters of all olaparib downregulated lncRNAs. Finally, we predicted that olaparib-modulated lncRNAs could further regulate several transcription factors and their subsequent target genes in melanoma, suggesting that olaparib may trigger a major shift in gene expression mediated by the regulation lncRNA. Globally, olaparib changed the lncRNA expression landscape during VM affecting angiogenesis-related genes.

scholarly journals Upregulation and cell specificity of C4 genes are derived from ancestral C3 gene regulatory networks

2020 ◽  
Author(s):  
Pallavi Singh ◽  
Sean R. Stevenson ◽  
Ivan Reyna-Llorens ◽  
Gregory Reeves ◽  
Tina B. Schreier ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cell Types ◽  
Chromatin Accessibility ◽  
Transcript Accumulation ◽  
Specific Expression ◽  
Cell Specificity ◽  
Distinct Cell ◽  
Gene Regulatory

ABSTRACTThe efficient C4 pathway is based on strong up-regulation of genes found in C3 plants, but also compartmentation of their expression into distinct cell-types such as the mesophyll and bundle sheath. Transcription factors associated with these phenomena have not been identified. To address this, we undertook genome-wide analysis of transcript accumulation, chromatin accessibility and transcription factor binding in C4Gynandropsis gynandra. From these data, two models relating to the molecular evolution of C4 photosynthesis are proposed. First, increased expression of C4 genes is associated with increased binding by MYB-related transcription factors. Second, mesophyll specific expression is associated with binding of homeodomain transcription factors. Overall, we conclude that during evolution of the complex C4 trait, C4 cycle genes gain cis-elements that operate in the C3 leaf such that they become integrated into existing gene regulatory networks associated with cell specificity and photosynthesis.

scholarly journals Revealing the Key Regulators of Cell Identity in the Human Adult Pancreas

2020 ◽  
Author(s):  
Lotte Vanheer ◽  
Andrea Alex Schiavo ◽  
Matthias Van Haele ◽  
Tine Haesen ◽  
Adrian Janiszewski ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Cell Types ◽  
List Type ◽  
Cell Identity ◽  
Pancreatic Cell ◽  
Human Adult ◽  
Gene Regulatory ◽  
Cellular Identity

SUMMARYCellular identity during development is under the control of transcription factors that form gene regulatory networks. However, the transcription factors and gene regulatory networks underlying cellular identity in the human adult pancreas remain largely unexplored. Here, we integrate multiple single-cell RNA sequencing datasets of the human adult pancreas, totaling 7393 cells, and comprehensively reconstruct gene regulatory networks. We show that a network of 142 transcription factors forms distinct regulatory modules that characterize pancreatic cell types. We present evidence that our approach identifies key regulators of cell identity in the human adult pancreas. We predict that HEYL and JUND are active in acinar and alpha cells, respectively, and show that these proteins are present in the human adult pancreas as well as in human induced pluripotent stem cell-derived pancreatic cells. The comprehensive gene regulatory network atlas can be explored interactively online. We anticipate our analysis to be the starting point for a more sophisticated dissection of how transcription factors regulate cell identity in the human adult pancreas. Furthermore, given that transcription factors are major regulators of embryo development and are often perturbed in diseases, a comprehensive understanding of how transcription factors work will be relevant in development and disease biology.HIGHLIGHTS-Reconstruction of gene regulatory networks for human adult pancreatic cell types-An interactive resource to explore and visualize gene expression and regulatory states-Predicting putative transcription factors driving pancreatic cell identity-HEYL and JUND as candidate regulators of acinar and alpha cell identity, respectively

scholarly journals The Role of Gene Conversion between Transposable Elements in Rewiring Regulatory Networks

2019 ◽  
Vol 11 (7) ◽  
pp. 1723-1729
Author(s):  
Jeffrey A Fawcett ◽  
Hideki Innan
Keyword(s):  
Transposable Elements ◽  
Gene Conversion ◽  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Alternative Mechanism ◽  
Beneficial Mutations ◽  
Future Studies ◽  
Cellular Processes ◽  
Gene Regulatory

Abstract Nature has found many ways to utilize transposable elements (TEs) throughout evolution. Many molecular and cellular processes depend on DNA-binding proteins recognizing hundreds or thousands of similar DNA motifs dispersed throughout the genome that are often provided by TEs. It has been suggested that TEs play an important role in the evolution of such systems, in particular, the rewiring of gene regulatory networks. One mechanism that can further enhance the rewiring of regulatory networks is nonallelic gene conversion between copies of TEs. Here, we will first review evidence for nonallelic gene conversion in TEs. Then, we will illustrate the benefits nonallelic gene conversion provides in rewiring regulatory networks. For instance, nonallelic gene conversion between TE copies offers an alternative mechanism to spread beneficial mutations that improve the network, it allows multiple mutations to be combined and transferred together, and it allows natural selection to work efficiently in spreading beneficial mutations and removing disadvantageous mutations. Future studies examining the role of nonallelic gene conversion in the evolution of TEs should help us to better understand how TEs have contributed to evolution.

scholarly journals A primate-specific retroviral enhancer wires the XACT lncRNA into the core pluripotency network in humans

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Miguel Casanova ◽  
Madeleine Moscatelli ◽  
Louis Édouard Chauvière ◽  
Christophe Huret ◽  
Julia Samson ◽  
...  
Keyword(s):  
Gene Regulatory Networks ◽  
Regulatory Networks ◽  
Endogenous Retroviruses ◽  
X Chromosomes ◽  
Regulatory Pathways ◽  
Gene Regulatory ◽  
Non Coding Rnas ◽  
Specific Regulation ◽  
Species Specific ◽  
And Function

AbstractTransposable elements (TEs) have been proposed to play an important role in driving the expansion of gene regulatory networks during mammalian evolution, notably by contributing to the evolution and function of long non-coding RNAs (lncRNAs). XACT is a primate-specific TE-derived lncRNA that coats active X chromosomes in pluripotent cells and may contribute to species-specific regulation of X-chromosome inactivation. Here we explore how different families of TEs have contributed to shaping the XACT locus and coupling its expression to pluripotency. Through a combination of sequence analysis across primates, transcriptional interference, and genome editing, we identify a critical enhancer for the regulation of the XACT locus that evolved from an ancestral group of mammalian endogenous retroviruses (ERVs), prior to the emergence of XACT. This ERV was hijacked by younger hominoid-specific ERVs that gave rise to the promoter of XACT, thus wiring its expression to the pluripotency network. This work illustrates how retroviral-derived sequences may intervene in species-specific regulatory pathways.

scholarly journals Cell-free gene-regulatory network engineering with synthetic transcription factors

2019 ◽  
Vol 116 (13) ◽  
pp. 5892-5901 ◽  
Author(s):  
Zoe Swank ◽  
Nadanai Laohakunakorn ◽  
Sebastian J. Maerkl
Keyword(s):  
Transcription Factors ◽  
High Throughput ◽  
Gene Regulatory Networks ◽  
Protein Interactions ◽  
Transcriptional Repression ◽  
Regulatory Networks ◽  
De Novo ◽  
Mechanistic Modeling ◽  
Free System ◽  
Gene Regulatory

Gene-regulatory networks are ubiquitous in nature and critical for bottom-up engineering of synthetic networks. Transcriptional repression is a fundamental function that can be tuned at the level of DNA, protein, and cooperative protein–protein interactions, necessitating high-throughput experimental approaches for in-depth characterization. Here, we used a cell-free system in combination with a high-throughput microfluidic device to comprehensively study the different tuning mechanisms of a synthetic zinc-finger repressor library, whose affinity and cooperativity can be rationally engineered. The device is integrated into a comprehensive workflow that includes determination of transcription-factor binding-energy landscapes and mechanistic modeling, enabling us to generate a library of well-characterized synthetic transcription factors and corresponding promoters, which we then used to build gene-regulatory networks de novo. The well-characterized synthetic parts and insights gained should be useful for rationally engineering gene-regulatory networks and for studying the biophysics of transcriptional regulation.

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