Role of Diversity-Generating Retroelements for Regulatory Pathway Tuning in Cyanobacteria

Abstract Background Cyanobacteria maintain extensive repertoires of regulatory genes that are vital for adaptation to environmental stress. Some cyanobacterial genomes have been noted to encode diversity-generating retroelements (DGRs), which promote protein hypervariation through localized retrohoming and codon rewriting in target genes. Past research has shown DGRs to mainly diversify proteins involved in cell-cell attachment or viral-host attachment within viral, bacterial, and archaeal lineages. However, these elements may be critical in driving variation for proteins involved in other core cellular processes. Results Members of 31 cyanobacterial genera encode at least one DGR, and together, their retroelements form a monophyletic clade of closely-related reverse transcriptases. This class of retroelements diversifies target proteins with unique domain architectures: modular ligand-binding domains often paired with a second domain that is linked to signal response or regulation. Comparative analysis indicates recent intragenomic duplication of DGR targets as paralogs, but also apparent intergenomic exchange of DGR components. The prevalence of DGRs and the paralogs of their targets is disproportionately high among colonial and filamentous strains of cyanobacteria. Conclusion We find that colonial and filamentous cyanobacteria have recruited DGRs to optimize a ligand-binding module for apparent function in signal response or regulation. These represent a unique class of hypervariable proteins, which might offer cyanobacteria a form of plasticity to adapt to environmental stress. This analysis supports the hypothesis that DGR-driven mutation modulates signaling and regulatory networks in cyanobacteria, suggestive of a new framework for the utility of localized genetic hypervariation.

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miRDRN – miRNA Disease Regulatory Network: A tool for exploring disease and tissue-specific microRNA regulatory networks

10.7287/peerj.preprints.27699v1 ◽

2019 ◽

Author(s):

Hsueh-Chuan Liu ◽

Yi-Shian Peng ◽

Hoong-Chien Lee

Keyword(s):

Web Service ◽

Regulatory Network ◽

Regulatory Networks ◽

Target Genes ◽

Gene Annotation ◽

Service Platform ◽

Tissue Specific ◽

Cellular Processes ◽

Specific Subset ◽

Pathway Gene

Background. MiRNA regulates cellular processes through acting on specific target genes. Hundreds of miRNAs and their target genes have been identified, as are many miRNA-disease associations. Cellular processes, including those related to disease, proceed through multiple interactions, are often organized into pathways among genes and gene products. Large databases on protein-protein interactions (PPIs) are available. Here, we have integrated the information mentioned above to build a web service platform, miRNA Disease Regulatory Network, or miRDRN, for users to construct disease and tissue-specific miRNA-protein regulatory networks. Methods. Data on human protein interaction, disease-associated miRNA, tumor-associated gene, miRNA targeted gene, molecular interaction and reaction network or pathway, gene ontology, gene annotation and gene product information, and gene expression were collected from publicly available databases and integrated. A complete set of regulatory sub-pathways (RSPs) having the form (M, T, G1, G2) were built from the integrated data and stored in the database part of miRDRN, where M is a disease-associated miRNA, T is its regulatory target gene, G1 (G2) is a gene/protein interacting with T (G1). Each sequence (T, G1, G2) was assigned a p-value weighted by the participation of the three genes in molecular interactions and reaction pathways. Results. A web service platform, miRDRN ( http://mirdrn.ncu.edu.tw/mirdrn/), was built to allow users to retrieve a disease and tissue-specific subset of RSPs, from which a miRNA regulatory network is constructed. miRDRN is a database that currently contains 6,973,875 p-valued sub-pathways associated with 119 diseases in 78 tissue types built from 207 diseases-associated miRNA regulating 389 genes, and a web tool that facilitates the construction and visualization of disease and tissue-specific miRNA-protein regulatory networks, for exploring single diseases, or for exploring the comorbidity of disease-pairs. As demonstrations, miRDRN was applied: to explore the single disease colorectal cancer (CRC), in which 26 novel potential CRC target genes were identified; to study the comorbidity of the disease-pair Alzheimer's disease-Type 2 diabetes (AD-T2D), in which 18 novel potential comorbid genes were identified; and, to explore possible causes that may shed light on recent failures of late-phase trials of anti-AD, BACE1 inhibitor drugs, in which genes downstream to BACE1 whose suppression may affect signal transduction were identified.

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Kinetic networks identify key regulatory nodes and transcription factor functions in early adipogenesis

10.1101/2021.11.17.469040 ◽

2021 ◽

Author(s):

Arun B Dutta ◽

Bao Ngyuen ◽

Warren D Anderson ◽

Ninad M Walavalkar ◽

Fabiana M Duarte ◽

...

Keyword(s):

Chromatin Structure ◽

Regulatory Networks ◽

Target Genes ◽

Gene Activation ◽

Compartment Model ◽

Chromatin Accessibility ◽

Regulate Gene Expression ◽

Cellular Processes ◽

Brown Adipose ◽

Regulatory Cascades

Sequence-specific transcription factors (TFs) bind DNA, modulate chromatin structure, regulate gene expression, and orchestrate transcription cascades. Activation and repression of TFs drive tightly controlled regulatory programs that lead to cellular processes such as differentiation. We measured chromatin accessibility and nascent transcription at seven time points over the first four hours of induced adipogenesis of 3T3-L1 mouse preadipocytes to construct dynamic gene regulatory networks. Regulatory networks describe successive waves of TF binding and dissociation followed by direct regulation of proximal genes. We identified 14 families of TFs that coordinate with and antagonize each other to regulate early adipogenesis. We developed a compartment model to quantify individual TF contributions to RNA polymerase initiation and pause release rates. Network analysis showed that the glucocorticoid receptor and AP1 drive immediate gene activation, including induction of Twist2. Twist2 is a highly interconnected node within the network and its expression leads to repression of target genes. Although Twist2's role in adipogenesis has not been previously appreciated, both Twist2 knockout mice and Setleis syndrome (Twist2-/-) patients lack subcutaneous and brown adipose tissue. We found that kinetic networks integrating chromatin structure and nascent transcription dynamics identify key genes, TF functions, and coordinate interactions within regulatory cascades.

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miRDRN—miRNA disease regulatory network: a tool for exploring disease and tissue-specific microRNA regulatory networks

PeerJ ◽

10.7717/peerj.7309 ◽

2019 ◽

Vol 7 ◽

pp. e7309

Author(s):

Hsueh-Chuan Liu ◽

Yi-Shian Peng ◽

Hoong-Chien Lee

Keyword(s):

Web Service ◽

Regulatory Network ◽

Regulatory Networks ◽

Mirna Target ◽

Target Genes ◽

Gene Annotation ◽

Biological Pathways ◽

Tissue Specific ◽

Cellular Processes ◽

Disease Pair

Background MicroRNA (miRNA) regulates cellular processes by acting on specific target genes, and cellular processes proceed through multiple interactions often organized into pathways among genes and gene products. Hundreds of miRNAs and their target genes have been identified, as are many miRNA-disease associations. These, together with huge amounts of data on gene annotation, biological pathways, and protein–protein interactions are available in public databases. Here, using such data we built a database and web service platform, miRNA disease regulatory network (miRDRN), for users to construct disease and tissue-specific miRNA-protein regulatory networks, with which they may explore disease related molecular and pathway associations, or find new ones, and possibly discover new modes of drug action. Methods Data on disease-miRNA association, miRNA-target association and validation, gene-tissue association, gene-tumor association, biological pathways, human protein interaction, gene ID, gene ontology, gene annotation, and product were collected from publicly available databases and integrated. A large set of miRNA target-specific regulatory sub-pathways (RSPs) having the form (T, G1, G2) was built from the integrated data and stored, where T is a miRNA-associated target gene, G1 (G2) is a gene/protein interacting with T (G1). Each sequence (T, G1, G2) was assigned a p-value weighted by the participation of the three genes in molecular interactions and reaction pathways. Results A web service platform, miRDRN (http://mirdrn.ncu.edu.tw/mirdrn/), was built. The database part of miRDRN currently stores 6,973,875 p-valued RSPs associated with 116 diseases in 78 tissue types built from 207 diseases-associated miRNA regulating 389 genes. miRDRN also provides facilities for the user to construct disease and tissue-specific miRNA regulatory networks from RSPs it stores, and to download and/or visualize parts or all of the product. User may use miRDRN to explore a single disease, or a disease-pair to gain insights on comorbidity. As demonstrations, miRDRN was applied: to explore the single disease colorectal cancer (CRC), in which 26 novel potential CRC target genes were identified; to study the comorbidity of the disease-pair Alzheimer’s disease-Type 2 diabetes, in which 18 novel potential comorbid genes were identified; and, to explore possible causes that may shed light on recent failures of late-phase trials of anti-AD, BACE1 inhibitor drugs, in which genes downstream to BACE1 whose suppression may affect signal transduction were identified.

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miRDRN – miRNA Disease Regulatory Network: A tool for exploring disease and tissue-specific microRNA regulatory networks

10.7287/peerj.preprints.27699 ◽

2019 ◽

Author(s):

Hsueh-Chuan Liu ◽

Yi-Shian Peng ◽

Hoong-Chien Lee

Keyword(s):

Web Service ◽

Regulatory Network ◽

Regulatory Networks ◽

Target Genes ◽

Gene Annotation ◽

Service Platform ◽

Tissue Specific ◽

Cellular Processes ◽

Specific Subset ◽

Pathway Gene

Background. MiRNA regulates cellular processes through acting on specific target genes. Hundreds of miRNAs and their target genes have been identified, as are many miRNA-disease associations. Cellular processes, including those related to disease, proceed through multiple interactions, are often organized into pathways among genes and gene products. Large databases on protein-protein interactions (PPIs) are available. Here, we have integrated the information mentioned above to build a web service platform, miRNA Disease Regulatory Network, or miRDRN, for users to construct disease and tissue-specific miRNA-protein regulatory networks. Methods. Data on human protein interaction, disease-associated miRNA, tumor-associated gene, miRNA targeted gene, molecular interaction and reaction network or pathway, gene ontology, gene annotation and gene product information, and gene expression were collected from publicly available databases and integrated. A complete set of regulatory sub-pathways (RSPs) having the form (M, T, G1, G2) were built from the integrated data and stored in the database part of miRDRN, where M is a disease-associated miRNA, T is its regulatory target gene, G1 (G2) is a gene/protein interacting with T (G1). Each sequence (T, G1, G2) was assigned a p-value weighted by the participation of the three genes in molecular interactions and reaction pathways. Results. A web service platform, miRDRN ( http://mirdrn.ncu.edu.tw/mirdrn/), was built to allow users to retrieve a disease and tissue-specific subset of RSPs, from which a miRNA regulatory network is constructed. miRDRN is a database that currently contains 6,973,875 p-valued sub-pathways associated with 119 diseases in 78 tissue types built from 207 diseases-associated miRNA regulating 389 genes, and a web tool that facilitates the construction and visualization of disease and tissue-specific miRNA-protein regulatory networks, for exploring single diseases, or for exploring the comorbidity of disease-pairs. As demonstrations, miRDRN was applied: to explore the single disease colorectal cancer (CRC), in which 26 novel potential CRC target genes were identified; to study the comorbidity of the disease-pair Alzheimer's disease-Type 2 diabetes (AD-T2D), in which 18 novel potential comorbid genes were identified; and, to explore possible causes that may shed light on recent failures of late-phase trials of anti-AD, BACE1 inhibitor drugs, in which genes downstream to BACE1 whose suppression may affect signal transduction were identified.

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MiRNA-145 and Its Direct Downstream Targets in Digestive System Cancers: A Promising Therapeutic Target

Current Pharmaceutical Design ◽

10.2174/1381612826666201029095702 ◽

2020 ◽

Vol 26 ◽

Author(s):

Yini Ma ◽

Xiu Cao ◽

Guojuan Shi ◽

Tianlu Shi

Keyword(s):

Digestive System ◽

Target Genes ◽

Malignant Neoplasm ◽

Vital Role ◽

Diagnostic Biomarkers ◽

Cellular Processes ◽

Promising Therapeutic Target ◽

Direct Target ◽

Potential Strategy

: MicroRNAs (miRNAs) play a vital role in the onset and development of many diseases, including cancers. Emerging evidence shows that numerous miRNAs have the potential to be used as diagnostic biomarkers for cancers, and miRNA-based therapy may be a promising therapy for the treatment of malignant neoplasm. MicroRNA-145 (miR-145) has been considered to play certain roles in various cellular processes, such as proliferation, differentiation and apoptosis, via modulating expression of direct target genes. Recent reports show that miR-145 participates in the progression of digestive system cancers, and plays crucial and novel roles for cancer treatment. In this review, we summarize the recent knowledge concerning the function of miR-145 and its direct targets in digestive system cancers. We discuss the potential role of miR-145 as valuable biomarkers for digestive system cancers and how miR-145 regulates these digestive system cancers via different targets to explore the potential strategy of targeting miR-145.

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EPEN-21. IMPAIRED NEURONAL-GLIAL FATE SPECIFICATION IN PEDIATRIC EPENDYMOMA REVEALED BY SINGLE-CELL RNA-SEQ

Neuro-Oncology ◽

10.1093/neuonc/noaa222.158 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii311-iii312

Author(s):

Bernhard Englinger ◽

Johannes Gojo ◽

Li Jiang ◽

Jens M Hübner ◽

McKenzie L Shaw ◽

...

Keyword(s):

Dna Methylation ◽

Single Cell ◽

Regulatory Networks ◽

Target Genes ◽

Target Identification ◽

Rna Seq ◽

Cell Models ◽

Pediatric Ependymoma ◽

Glial Fate ◽

Anatomic Locations

Abstract Ependymoma represents a heterogeneous disease affecting the entire neuraxis. Extensive molecular profiling efforts have identified molecular ependymoma subgroups based on DNA methylation. However, the intratumoral heterogeneity and developmental origins of these groups are only partially understood, and effective treatments are still lacking for about 50% of patients with high-risk tumors. We interrogated the cellular architecture of ependymoma using single cell/nucleus RNA-sequencing to analyze 24 tumor specimens across major molecular subgroups and anatomic locations. We additionally analyzed ten patient-derived ependymoma cell models and two patient-derived xenografts (PDXs). Interestingly, we identified an analogous cellular hierarchy across all ependymoma groups, originating from undifferentiated neural stem cell-like populations towards different degrees of impaired differentiation states comprising neuronal precursor-like, astro-glial-like, and ependymal-like tumor cells. While prognostically favorable ependymoma groups predominantly harbored differentiated cell populations, aggressive groups were enriched for undifferentiated subpopulations. Projection of transcriptomic signatures onto an independent bulk RNA-seq cohort stratified patient survival even within known molecular groups, thus refining the prognostic power of DNA methylation-based profiling. Furthermore, we identified novel potentially druggable targets including IGF- and FGF-signaling within poorly prognostic transcriptional programs. Ependymoma-derived cell models/PDXs widely recapitulated the transcriptional programs identified within fresh tumors and are leveraged to validate identified target genes in functional follow-up analyses. Taken together, our analyses reveal a developmental hierarchy and transcriptomic context underlying the biologically and clinically distinct behavior of ependymoma groups. The newly characterized cellular states and underlying regulatory networks could serve as basis for future therapeutic target identification and reveal biomarkers for clinical trials.

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The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells

Cancers ◽

10.3390/cancers13061239 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1239

Author(s):

Leila Jahangiri ◽

Tala Ishola ◽

Perla Pucci ◽

Ricky M. Trigg ◽

Joao Pereira ◽

...

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Progression ◽

Regulatory Networks ◽

Epithelial To Mesenchymal Transition ◽

Tumour Microenvironment ◽

Repair Capacity ◽

Mesenchymal Transition ◽

Cellular Processes

Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, epithelial-to-mesenchymal transition (EMT), and signalling pathways.

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Epigenetic Methylations on N6-Adenine and N6-Adenosine with the same Input but Different Output

International Journal of Molecular Sciences ◽

10.3390/ijms20122931 ◽

2019 ◽

Vol 20 (12) ◽

pp. 2931 ◽

Cited By ~ 4

Author(s):

Zhiqing Li ◽

Ping Zhao ◽

Qingyou Xia

Keyword(s):

Genetic Information ◽

Target Genes ◽

Technological Development ◽

Wide Spectrum ◽

Functional Identification ◽

Methyl Group ◽

Cellular Processes ◽

Dna And Rna ◽

Future Challenges ◽

Detection Strategies

Epigenetic modifications on individual bases in DNA and RNA can encode inheritable genetic information beyond the canonical bases. Among the nucleic acid modifications, DNA N6-methadenine (6mA) and RNA N6-methyladenosine (m6A) have recently been well-studied due to the technological development of detection strategies and the functional identification of modification enzymes. The current findings demonstrate a wide spectrum of 6mA and m6A distributions from prokaryotes to eukaryotes and critical roles in multiple cellular processes. It is interesting that the processes of modification in which the methyl group is added to adenine and adenosine are the same, but the outcomes of these modifications in terms of their physiological impacts in organisms are quite different. In this review, we summarize the latest progress in the study of enzymes involved in the 6mA and m6A methylation machinery, including methyltransferases and demethylases, and their functions in various biological pathways. In particular, we focus on the mechanisms by which 6mA and m6A regulate the expression of target genes, and we highlight the future challenges in epigenetic regulation.

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