Growing recognition of the pivotal role microglia play in neurodegenerative and neuroinflammatory disorders has accentuated the need to characterize their function in health and disease. Studies in mouse have applied transcriptome‐wide profiling of microglia to reveal key features of microglial ontogeny, functional profile, and phenotypic diversity. While similar, human microglia exhibit clear differences to their mouse counterparts, underlining the need to develop a better understanding of the human microglial profile. On examining published microglia gene signatures, limited consistency was observed between studies. Hence, we sought to derive a core microglia signature of the human central nervous system (CNS), through a comprehensive analysis of existing transcriptomic datasets. Nine datasets derived from cells and tissues, isolated from various regions of the CNS across numerous donors, were subjected independently to an unbiased correlation network analysis. From each dataset, a list of coexpressing genes corresponding to microglia was identified, with 249 genes highly conserved between them. This core signature included known microglial markers, and compared with other signatures provides a gene set specific to microglia in the context of the CNS. The utility of this signature was demonstrated by its use in detecting qualitative and quantitative region‐specific alterations in aging and Alzheimer's disease. These analyses highlighted the reactive response of microglia in vulnerable brain regions such as the entorhinal cortex and hippocampus, additionally implicating pathways associated with disease progression. We believe this resource and the analyses described here, will support further investigations to the contribution of human microglia in CNS health and disease.
cilia are complex microtubule-based organelles essential to a range of processes associated with embryogenesis and tissue homeostasis. Mutations in components of these organelles or those involved in their assembly may result in a diverse set of diseases collectively known as ciliopathies. Accordingly, many cilia-associated proteins have been described, while those distinguishing cilia subtypes are poorly defined. Here we set out to define genes associated with motile cilia in humans based on their transcriptional signature. To define the signature, we performed network deconvolution of transcriptomics data derived from tissues possessing motile ciliated cell populations. for each tissue, genes coexpressed with the motile cilia-associated transcriptional factor, FOXJ1, were identified. The consensus across tissues provided a transcriptional signature of 248 genes. To validate these, we examined the literature, databases (cilDB, centrosomeDB, ciliacarta and Syscilia), single cell RnA-Seq data, and the localisation of mRnA and proteins in motile ciliated cells. in the case of six poorly characterised signature genes, we performed new localisation experiments on ARMC3, EFCAB6, FAM183A, MYCBPAP, RIBC2 and VWA3A. in summary, we report a set of motile cilia-associated genes that helps shape our understanding of these complex cellular organelles. Cilia and flagella are related organelles that facilitate an array of cellular functions. In eukaryotes, the core structural components of cilia includes: the axoneme, a microtubular protrusion from the cell surface composed of an array of microtubules; a centrosomal core, comprised of a mother (basal body) and daughter centriole 1,2 anchored to the base of the axoneme, and the centriole-associated distal and sub-distal appendages 3. Generally, cilia can be subdivided into non-motile primary cilia, in which nine microtubules constitute the axoneme (9 + 0) and motile cilia, characterised by an additional central pair of microtubules (9 + 2) 4-6. Primary cilia are found on most cell types, where their principal role is as a sensor of the cell's microenvironment 7. In contrast, motile cilia are restricted to specific cell populations. Flagellum function as a single large 'propeller' and in eukaryotes are found exclusively on spermatocytes where they drive cell motility. Other motile cilia are found in large numbers on the apical surface of certain types of epithelial cells, where their coordinated beating displaces the luminal contents over the epithelial surface, e.g. the clearance of mucus in the respiratory tract. Whilst there are a set of core proteins common to all cilia, there are also structural and regulatory elements unique to motile cilia which underpin their distinct functional activity 8,9. Motile cilia play a vital role in human development and homeostasis, and there is a growing list of ciliopathies (cilia-related diseases) associated with mutations of ciliary assembly proteins and protein components of these organelles. These include defects in left-right patterning...
Quantitative and qualitative data derived from the analysis of genomes, genes, proteins or metabolites from tissue or cells are currently generated in huge volumes during biomedical research. Graphia is an open-source platform created for the graph-based analysis of such complex data, e.g. transcriptomics, proteomics, genomics data. The software imports data already defined as a network or a similarity matrix and is designed to rapidly visualise very large graphs in 2D or 3D space, providing a wide range of functionality for graph exploration. An extensive range of analysis algorithms, routines for graph transformation, and options for the visualisation of node and edge attributes are also available. Graphia’s core is extensible through the deployment of plugins, supporting rapid development of additional computational analyses and features necessary for a given analysis task or data source. A plugin for correlation network analysis is distributed with the core application, to support the generation of correlation graphs from any tabular matrix of continuous or discrete values. This provides a powerful analysis solution for the interpretation of high-dimensional data from many sources. Several use cases of Graphia are described, to showcase its wide range of applications. Graphia runs on all major desktop operating systems and is freely available to download from https://graphia.app/.
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