Insights into mammalian transcription control by systematic analysis of ChIP sequencing data

Abstract Background Transcription regulation is a major controller of gene expression dynamics during development and disease, where transcription factors (TFs) modulate expression of genes through direct or indirect DNA interaction. ChIP sequencing has become the most widely used technique to get a genome wide view of TF occupancy in a cell type of interest, mainly due to established standard protocols and a rapid decrease in the cost of sequencing. The number of available ChIP sequencing data sets in public domain is therefore ever increasing, including data generated by individual labs together with consortia such as the ENCODE project. Results A total of 1735 ChIP-sequencing datasets in mouse and human cell types and tissues were used to perform bioinformatic analyses to unravel diverse features of transcription control. 1- We used the Heat*seq webtool to investigate global relations across the ChIP-seq samples. 2- We demonstrated that factors have a specific genomic location preferences that are, for most factors, conserved across species. 3- Promoter proximal binding of factors was more conserved across cell types while the distal binding sites are more cell type specific. 4- We identified combinations of factors preferentially acting together in a cellular context. 5- Finally, by integrating the data with disease-associated gene loci from GWAS studies, we highlight the value of this data to associate novel regulators to disease. Conclusion In summary, we demonstrate how ChIP sequencing data integration and analysis is powerful to get new insights into mammalian transcription control and demonstrate the utility of various bioinformatic tools to generate novel testable hypothesis using this public resource

DNA methylation signal has a major role in the response of human breast cancer cells to the microenvironment

International audienceBreast cancer-associated fibroblasts (CAFs) have a crucial role in tumor initiation, metastasis and therapeutic resistance by secreting various growth factors, cytokines, protease and extracellular matrix components. Soluble factors secreted by CAFs are involved in many pathways including inflammation, metabolism, proliferation and epigenetic modulation, suggesting that CAF-dependent reprograming of cancer cells affects a large set of genes. This paracrine signaling has an important role in tumor progression, thus deciphering some of these processes could lead to relevant discoveries with subsequent clinical implications. Here, we investigated the mechanisms underlying the changes in gene expression patterns associated with the cross-talk between breast cancer cells and the stroma. From RNAseq data obtained from breast cancer cell lines grown in presence of CAF-secreted factors, we identified 372 upregulated genes, exhibiting an expression level positively correlated with the stromal content of breast cancer specimens. Furthermore, we observed that gene expression changes were not mediated through significant DNA methylation changes. Nevertheless, CAF-secreted factors but also stromal content of the tumors remarkably activated specific genes characterized by a DNA methylation pattern: hypermethylation at transcription start site and shore regions. Experimental approaches (inhibition of DNA methylation, knockdown of methyl-CpG-binding domain protein 2 and chromatin immunoprecipitation assays) indicated that this set of genes was epigenetically controlled. These data elucidate the importance of epigenetics marks in the cancer cell reprogramming induced by stromal cell and indicated that the interpreters of the DNA methylation signal have a major role in the response of the cancer cells to the microenvironment

Inferring livestock movement networks from archived data to support infectious disease control in developing countries

AbstractThe use of network analysis to support livestock disease control in low middle-income countries (LMICs) has historically been hampered by the cost of generating empirical data in the absence of animal movement recording schemes. To fill this gap, methods which exploit freely available demographic and archived molecular data can be used to generate livestock networks based on gravity and phylogeographic modelling techniques, respectively. However, questions remain on the performance of these methods in capturing the topology of empirical networks. Here, we compare output from these network methodologies to a network constructed from either empirical data or randomly generated data. To facilitate this comparison, the spread of infectious diseases was simulated, it is this evaluation that demonstrates their potential utility to inform robust livestock disease control strategies.The molecular network was the closest approximation to the empirical network, both in relation to topological and epidemic characteristics, whereas size of epidemics in the gravity network tended to be larger, better agreement across all three networks was observed when; a) total nodes infected, b) percentage infection take off were compared. These methods consistently identified the same important animal movement and trade hotspots as the empirical networks. We therefore consider this proof-of-concept that demographic data such as censuses and archived molecular data could be repurposed to inform livestock disease management in LMICs.Author summaryLive animal movements in Africa represent a significant risk of transmission and spread of infectious diseases in livestock populations, and therefore, have direct implications on the food security of the continent. Here we explore the potential utility of available data to support control strategies, by comparing movement networks inferred from such data i.e. census and pathogen molecular data using gravity modelling and phylogeography respectively. Their utility is evaluated by comparing their topology and disease spread characteristics to empirical live animal movement. Based on our results, we posit that archived data can be repurposed to support infectious disease control on the African continent.</jats:sec

The PLA2R1-JAK2 pathway upregulates ERRα and its mitochondrial program to exert tumor-suppressive action

Little is known about the biological role of the phospholipase A2 receptor (PLA2R1) transmembrane protein. In recent years, PLA2R1 has been shown to have an important role in regulating tumor-suppressive responses via JAK2 activation, but the underlying mechanisms are largely undeciphered. In this study, we observed that PLA2R1 increases the mitochondrial content, judged by increased levels of numerous mitochondrial proteins, of the mitochondrial structural component cardiolipin, of the mitochondrial DNA content, and of the mitochondrial DNA replication and transcription factor TFAM. This effect of PLA2R1 relies on a transcriptional program controlled by the estrogen-related receptor alpha1 (ERRα) mitochondrial master regulator. Expression of ERRα and of its nucleus-encoded mitochondrial targets is upregulated upon PLA2R1 ectopic expression, and this effect is mediated by JAK2. Conversely, downregulation of PLA2R1 decreases the level of ERRα and of its nucleus-encoded mitochondrial targets. Finally, blocking the ERRα-controlled mitochondrial program largely inhibits the PLA2R1-induced tumor-suppressive response. Together, our data document ERRα and its mitochondrial program as downstream effectors of the PLA2R1-JAK2 pathway leading to oncosuppression

The PLA2R1-JAK2 pathway upregulates ERRα and its mitochondrial program to exert tumor-suppressive action

Little is known about the biological role of the phospholipase A2 receptor (PLA2R1) transmembrane protein. In recent years, PLA2R1 has been shown to have an important role in regulating tumor-suppressive responses via JAK2 activation, but the underlying mechanisms are largely undeciphered. In this study, we observed that PLA2R1 increases the mitochondrial content, judged by increased levels of numerous mitochondrial proteins, of the mitochondrial structural component cardiolipin, of the mitochondrial DNA content, and of the mitochondrial DNA replication and transcription factor TFAM. This effect of PLA2R1 relies on a transcriptional program controlled by the estrogen-related receptor alpha1 (ERRα) mitochondrial master regulator. Expression of ERRα and of its nucleus-encoded mitochondrial targets is upregulated upon PLA2R1 ectopic expression, and this effect is mediated by JAK2. Conversely, downregulation of PLA2R1 decreases the level of ERRα and of its nucleus-encoded mitochondrial targets. Finally, blocking the ERRα-controlled mitochondrial program largely inhibits the PLA2R1-induced tumor-suppressive response. Together, our data document ERRα and its mitochondrial program as downstream effectors of the PLA2R1-JAK2 pathway leading to oncosuppression

Specifying clinical assessment schedules for the European framework of rehabilitation service types : the perspective of the physical and rehabilitation medicine section and Board of the European Union of Medical specialists

INTRODUCTION: In light of global mandates and in recognition of the value of data collection and reporting based on the International Classification of Functioning, Disability and Health (ICF), the UEMS PRM Section and Board established an action plan to implement the ICF in Physical and Rehabilitation Medicine, rehabilitation and health care at large. This includes, among other steps, the development of a framework of rehabilitation service types for Europe (European Framework) and corresponding clinical assessment schedules (CLASs) for each service type. A CLAS encompasses the recommendation for what aspects of functioning to document, for whom and when, and the data collection tools to use. The objective of this paper is to report on the development of the CLASs for the European Framework developed in Stockholm in 2018, with focus on what to document. METHODS: Involving UEMS PRM delegates across European regions, a multistage Delphi process comprised the development of an initial proposal of the CLASs (i.e. default and optional ICF Sets to document), two feedback (pre- and post-Stockholm) rounds via e-mail, and a deliberation by the UEMS PRM during its March 2019 meeting in Budapest. In both Delphi rounds, participants were asked whether the initially proposed default and optional ICF Sets represent what is currently documented at an exemplary service provider in the country or in consideration of their own expertise. The European Framework was revised between the two Delphi rounds, requiring a revision of the CLAS proposal accordingly. Participants were additionally asked whether they support the suggested ICF Sets as the specification of the CLAS. Level of support (strong = ≥80%, moderate = between 80-60%, weak =≤59%) was calculated as the percentage of countries supporting the suggested CLAS over the number of responding countries. The results of the post-Stockholm round were presented for discussion, revision and approval at the Budapest meeting. RESULTS: Pre-Stockholm Delphi round: due to low response rate only a summary of comments made by the responding countries was provided as reference information for the post-Stockholm round. Post-Stockholm Delphi round: results indicated moderate to strong support for the proposed CLASs. Deliberation Budapest Meeting - Motions for specific revisions to the CLASs based on the results of the Post-Stockholm round were predominately accepted. With additional minor revisions, the UEMS PRM General Assembly approved a version of the CLASs for the European Framework. CONCLUSIONS: To kick-off the implementation of these CLASs, UEMS PRM plans demonstration projects in at least one rehabilitation facility in each delegate country that exemplifies the rehabilitation service types of the European Framework which exist in the respective country. The demonstration projects are intended to orient service providers and clinicians to the CLASs and illustrate how the CLASs can be implemented