Prediction of DNA binding motifs from 3D models of transcription factors; identifying TLX3 regulated genes

Pujato, Mario; Kieken, Fabien; Skiles, Amanda A.; Tapinos, Nikos; Fiser, András

doi:10.1093/nar/gku1228

Cited by 94 publications

(79 citation statements)

References 70 publications

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“…We focused on TFs that were either (i) highly abundant in each gland type at each developmental stage, (ii) had salivary gland specific expression, or (iii) had been previously implicated in salivary gland development, disease or cancer ( Figure 3A , Table S4 ). More than (Pujato et al, 2014) ) expression levels across fetal and mature salivary gland tissues. Four categories of transcription factors are shown in the heatmap: Transcription factors that are (i) differentially expressed (P<0.0001) among mature glands, (ii) abundant (>2000, normalized gene count in DESeq) in adult or fetal glands, (iii) previously been associated with organogenesis , and (iv) salivary-gland-specific (that is, >100 normalized gene count from DESeq in the salivary glands but show negligible expression in all 53 GTEx tissue).…”

Section: The Diverse Transcription Factor (Tf) Repertoire Of Mature Smentioning

confidence: 99%

Functional specialization of human salivary glands and origins of proteins intrinsic to human saliva

Saitou

Gaylord²,

et al. 2020

Preprint

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Salivary proteins facilitate food perception and digestion, maintain the integrity of the mineralized tooth and oral epithelial surfaces, and shield the oro-digestive tract from environmental hazards and invading pathogens. Saliva, as one of the easiest to collect body fluids, also serves in diagnostic applications, with its proteins providing a window to body health. However, despite the availability of the human saliva proteome, the origins of individual proteins remain unclear. To bridge this gap, we analyzed the transcriptomes of 27 tissue samples derived from the three major types of human adult and fetal salivary glands and integrated these data with the saliva proteome and the proteomes and transcriptomes of 28+ other human organs, with tissue expression confirmed by 3D microscopy. Using these tools, we have linked saliva proteins to their source for the first time, an outcome with significant implications for basic research and diagnostic applications. Furthermore, our study represents the first comparative transcriptomic analysis of human adult and fetal exocrine organs, providing evidence that functional specialization occurs late in salivary gland development, and is driven mainly by the transcription of genes encoding secreted saliva proteins. Moreover, we found that dosage of abundant saliva proteins secreted by the salivary glands is primarily regulated at the transcriptional level, and that secreted proteins can be synthesized by distinct subsets of serous acinar cells, revealing hitherto unrecognized heterogeneity in the acinar cell lineage. Our results reveal the functional underpinnings of these secretory organs, paving the way for future investigations into saliva biology and pathology. SIGNIFICANCE STATEMENTSaliva facilitates the perception and digestion of food while regulating the homeostasis of microbes in the mouth and their transduction to the digestive tract. Proteins in saliva fluid are responsible for these diverse and important functions. To understand the glandular origins of proteins in saliva, we performed the hitherto most comprehensive investigation of gene expression in healthy human salivary glands. Our results revealed that each mature salivary gland type contributes a distinct repertoire of proteins to saliva. We provide evidence that these unique, gland-specific secreted protein profiles emerge late in gland development. Our results suggest that the origins of salivary proteins in whole mixed saliva can be parsed out only through an integrative analysis of both protein and RNA levels.

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Section: The Diverse Transcription Factor (Tf) Repertoire Of Mature Smentioning

confidence: 99%

Functional specialization of human salivary glands and origins of proteins intrinsic to human saliva

Saitou

Gaylord²,

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Genes involved in immune-associated pathways of the top ve most signi cantly (p < 0.05) enriched pathways from each analysis were selected and combined to analyse further. Potential transcription factors for these genes were retrieved from Tf2DNA database [46].…”

Section: Analysis Of Mrna Expressionmentioning

confidence: 99%

Genetic deletion of microRNA-22 blunts the inflammatory transcriptional response to status epilepticus and exacerbates epilepsy in mice

Silva

Reschke

Nguyen

et al. 2020

Preprint

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MicroRNAs perform important roles in the post-transcriptional regulation of gene expression. Sequencing as well as functional studies using antisense oligonucleotides, indicate important roles for microRNAs during the development of epilepsy through targeting transcripts involved in neuronal structure, gliosis and inflammation. MicroRNA-22 (miR-22) has been reported to protect against the development of epileptogenic brain networks through suppression of neuroinflammatory signalling. Here, we used mice with a genetic deletion of miR-22 to extend these insights. Mice lacking miR-22 displayed normal behaviour and brain structure and developed similar status epilepticus after intraamygdala kainic acid compared to wildtype animals. Continuous EEG monitoring after status epilepticus revealed an accelerated and exacerbated epilepsy phenotype whereby spontaneous seizures began sooner, occurred more frequently and were of longer duration in miR-22-deficient mice. RNA sequencing analysis of the hippocampus during the period of epileptogenesis revealed a specific suppression of inflammatory signalling in the hippocampus of miR-22-deficient mice. Taken together, these findings indicate a role for miR-22 in establishing early inflammatory responses to status epilepticus. Inflammatory signalling may serve anti-epileptogenic functions and cautions the timing of anti-inflammatory interventions for the treatment of status epilepticus.

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“…The GRN for C. elegans embryo data set was obtained from TF-gene interactions for C. elegans in TF2DNA database [34], where TF binding motifs and their regulated genes were identified by calculating the binding affinity based on the known 3D structure of TF-DNA complexes. The GRN for C. elegans was composed of 355,080 edges from 48 TFs to 15,738 genes.…”

Section: Gene Regulatory Networkmentioning

confidence: 99%

DeltaNeTS+: Elucidating the mechanism of drugs and diseases using gene expression and transcriptional regulatory networks

Noh

Ziyi

Chrysinas

et al. 2019

Preprint

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Background: Knowledge on the molecular targets of diseases and drugs is crucial for elucidating disease pathogenesis and mechanism of action of drugs, and for driving drug discovery and treatment formulation. In this regard, high-throughput gene transcriptional profiling has become a leading technology, generating whole-genome data on the transcriptional alterations caused by diseases or drug compounds. However, identifying direct gene targets, especially in the background of indirect (downstream) effects, based on differential gene expressions is difficult due to the complexity of gene regulatory network governing the gene transcriptional processes. Results:In this work, we developed a network analysis method, called DeltaNeTS+, for inferring direct gene targets of drugs and diseases from gene transcriptional profiles.DeltaNeTS+ relies on a gene regulatory network model to identify direct perturbations to the transcription of genes. Importantly, DeltaNeTS+ is able to combine both steady-state and timecourse gene expression profiles, as well as to leverage information on the gene network structure that is increasingly becoming available for a multitude of organisms, including human. We demonstrated the power of DeltaNeTS+ in predicting gene targets using gene expression data in complex organisms, including Caenorhabditis elegans and human cell lines (T-cell and Calu-3).More specifically, in an application to time-course gene expression profiles of influenza A H1N1 (swine flu) and H5N1 (avian flu) infection, DeltaNeTS+ shed light on the key differences of dynamic cellular perturbations caused by the two influenza strains. Conclusion:DeltaNeTS+ is an enabling tool to infer gene transcriptional perturbations caused by diseases and drugs from gene transcriptional profiles. By incorporating available information on gene network structure, DeltaNeTS+ produces accurate predictions of direct gene targets from

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Prediction of DNA binding motifs from 3D models of transcription factors; identifying TLX3 regulated genes

Cited by 94 publications

References 70 publications

Functional specialization of human salivary glands and origins of proteins intrinsic to human saliva

Functional specialization of human salivary glands and origins of proteins intrinsic to human saliva

Genetic deletion of microRNA-22 blunts the inflammatory transcriptional response to status epilepticus and exacerbates epilepsy in mice

DeltaNeTS+: Elucidating the mechanism of drugs and diseases using gene expression and transcriptional regulatory networks

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