Computational Identification of Master Regulators Influencing Trypanotolerance in Cattle

Rajavel, Abirami; Schmitt, Armin O.; Gültaş, Mehmet

doi:10.3390/ijms22020562

Cited by 3 publications

(7 citation statements)

References 161 publications

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“…Similar to previous studies [ 40 , 47 , 48 , 49 , 50 , 51 ], we detected upstream regulators that regulate a set of DEGs through concerted coordination of TFs and intermediary modulators. More precisely, these so-called master regulators (key nodes) are found on top of the regulatory hierarchy of complex regulatory networks, leading to the finely tuned gene expression of a gene set.…”

Section: Methodssupporting

confidence: 86%

Comparative Investigation of Gene Regulatory Processes Underlying Avian Influenza Viruses in Chicken and Duck

Klees

Schlüter

Schellhorn

et al. 2022

Biology

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The avian influenza virus (AIV) mainly affects birds and not only causes animals’ deaths, but also poses a great risk of zoonotically infecting humans. While ducks and wild waterfowl are seen as a natural reservoir for AIVs and can withstand most virus strains, chicken mostly succumb to infection with high pathogenic avian influenza (HPAI). To date, the mechanisms underlying the susceptibility of chicken and the effective immune response of duck have not been completely unraveled. In this study, we investigate the transcriptional gene regulation underlying disease progression in chicken and duck after AIV infection. For this purpose, we use a publicly available RNA-sequencing dataset from chicken and ducks infected with low-pathogenic avian influenza (LPAI) H5N2 and HPAI H5N1 (lung and ileum tissues, 1 and 3 days post-infection). Unlike previous studies, we performed a promoter analysis based on orthologous genes to detect important transcription factors (TFs) and their cooperation, based on which we apply a systems biology approach to identify common and species-specific master regulators. We found master regulators such as EGR1, FOS, and SP1, specifically for chicken and ETS1 and SMAD3/4, specifically for duck, which could be responsible for the duck’s effective and the chicken’s ineffective immune response.

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Section: Methodssupporting

confidence: 86%

Comparative Investigation of Gene Regulatory Processes Underlying Avian Influenza Viruses in Chicken and Duck

Klees

Schlüter

Schellhorn

et al. 2022

Biology

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“…In this section, we illustrate an overview of the analyses to highlight the difference between our previous studies [37,38] and the current study. Simultaneously this overview shows how this present study complements our previous studies.…”

Section: Methodsmentioning

confidence: 99%

“…Particularly, by considering the AAT disease development as a multi-stage progression process, we investigated Monotonically Expressed Genes (MEGs) to capture the complete progression process of the disease. As a result of our previous studies [37,38], we reported several transcription factors (TFs), their co-operations and master regulators governing the upstream molecular mechanism during the infection. Despite the rich literature on this disease, there is still a need for further investigation of genetic mechanisms of the regulatory processes addressing the complex interplay between regulatory SNPs, their corresponding gene expression and the downstream effectors in association with the AAT disease.…”

Section: Introductionmentioning

confidence: 97%

“…To decipher the underlying regulatory mechanisms determining trypanosusceptibility/trypanotolerance of these cattle breeds, we have recently analysed a time-series gene expression data set of the two cattle breeds [37,38]. Particularly, by considering the AAT disease development as a multi-stage progression process, we investigated Monotonically Expressed Genes (MEGs) to capture the complete progression process of the disease.…”

Section: Introductionmentioning

confidence: 99%

“…Our first computational study (middle box in blue-dotted lines) highlighted the transcription factor co-operations associated with the AAT disease progression[37]. In our second study (top box in black dashed lines), we performed an upstream analysis to detect master regulators and over-represented upstream pathways related to AAT[38]. In the current study (bottom box in red dashed lines), we focus on the downstream analysis to decipher the complex interplay of regulatory SNPs (rSNPs), their related gene expression and their corresponding downstream effectors, which regulate a multitude of signal transduction pathways during the AAT disease progression.…”

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confidence: 99%

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Deciphering the Molecular Mechanism Underlying African Animal Trypanosomiasis by Means of the 1000 Bull Genomes Project Genomic Dataset

Rajavel

Klees

Hui

et al. 2022

Biology

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African Animal Trypanosomiasis (AAT) is a neglected tropical disease and spreads by the vector tsetse fly, which carries the infectious Trypanosoma sp. in their saliva. Particularly, this parasitic disease affects the health of livestock, thereby imposing economic constraints on farmers, costing billions of dollars every year, especially in sub-Saharan African countries. Mainly considering the AAT disease as a multistage progression process, we previously performed upstream analysis to identify transcription factors (TFs), their co-operations, over-represented pathways and master regulators. However, downstream analysis, including effectors, corresponding gene expression profiles and their association with the regulatory SNPs (rSNPs), has not yet been established. Therefore, in this study, we aim to investigate the complex interplay of rSNPs, corresponding gene expression and downstream effectors with regard to the AAT disease progression based on two cattle breeds: trypanosusceptible Boran and trypanotolerant N’Dama. Our findings provide mechanistic insights into the effectors involved in the regulation of several signal transduction pathways, thereby differentiating the molecular mechanism with regard to the immune responses of the cattle breeds. The effectors and their associated genes (especially MAPKAPK5, CSK, DOK2, RAC1 and DNMT1) could be promising drug candidates as they orchestrate various downstream regulatory cascades in both cattle breeds.

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Investigation of the Regulatory Processes of Gene Expression in Animal and Plant Sciences

Wilhelmi

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Transcriptional regulation of gene expression in higher organisms is fundamental for numerous biological processes. These processes are mainly controlled by a special class of regulatory proteins, the transcription factors (TFs), and their combinatorial interplay. Various genetic programs, such as environmental adaptation, tissue development, or disease control, are governed by the binding of TFs to short DNA motifs, called transcription factor binding sites (TFBS), in the regulatory regions of their target genes. Single nucleotide polymorphisms (SNPs) located in promoter regions can alter TFBSs leading to a change in the binding affinity of TFs and, thus, affect gene expression. Such SNPs are referred to as regulatory SNPs (rSNPs). In recent years, rSNPs have come into the focus of research, and the underlying mechanisms resulting in a differential gene expression have been studied for many specific traits and diseases mainly in humans or model organisms, but also in agricultural species. However, these studies mostly concentrate on single regulatory variants and do not include systematic analyses. Thus, there is still a lack of such comprehensive analyses and genome-wide collections of rSNPs, and to date, only few tools and databases are available for livestock or crop species. In this work, I developed a pipeline for the detection of rSNPs and created the databases agReg-SNPdb and agReg-SNPdb-Plants, storing genome-wide collections of rSNPs and their predicted effects on TF binding for agricultural animal and plant species, respectively. agReg-SNPdb includes seven livestock and domestic species, namely cattle, pig, chicken, sheep, horse, goat, and dog and agReg-SNPdb-Plants includes 13 crop species and subspecies, namely African rice, Asian rice (with its subspecies Indica and Japonica), barley, bread wheat, durum wheat, grape, maize, rapeseed, sorghum, sunflower, tomato, and wild rice. Out of all species stored in agReg-SNPdb-Plants, rapeseed holds a special role. In contrast to the remaining species, where I used the data from Ensembl Plants as basis, in rapeseed, to date, there is no genome-wide collection of SNPs available. Therefore, I used a previously published data set based on different resequenced Brassica napus L. cultivars for the identification of rSNPs in agReg-SNPdb-Plants. Based on this data set, I investigated the regulatory mechanisms in two cultivars, namely Zhongshuang11 (ZS11), a so-called double-low accession with low content of erucic acid and glucosinolate, which is characterized by high oil content, and Zhongyou821 (ZY821), a so-called double-high accession with high content of erucic acid and glucosinolate, which is characterized by low oil content. In this way, I demonstrate the application of rSNPs together with multi-omics data to perform a systematic analysis of the complex interplay between rSNPs, TFs, and differentially expressed genes (DEGs) in four tissues (flower, leaf, stem, and root) which are underlying the oil content and -quality in rapeseed. viii Es hat mir großen Spaß ...

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Computational Identification of Master Regulators Influencing Trypanotolerance in Cattle

Cited by 3 publications

References 161 publications

Comparative Investigation of Gene Regulatory Processes Underlying Avian Influenza Viruses in Chicken and Duck

Comparative Investigation of Gene Regulatory Processes Underlying Avian Influenza Viruses in Chicken and Duck

Deciphering the Molecular Mechanism Underlying African Animal Trypanosomiasis by Means of the 1000 Bull Genomes Project Genomic Dataset

Investigation of the Regulatory Processes of Gene Expression in Animal and Plant Sciences

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