Biology subjects

Freeman, T.

Publications and source records attributed to Freeman, T..

3 recordsLinked to original sources

bioRxiv2018

A core transcriptional signature of human microglia: derivation and utility in describing region-dependent alterations associated with Alzheimer’s disease

Growing recognition of the pivotal role microglia play in neurodegenerative and neuroinflammatory disorders has accentuated the need to better 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. Whilst similar in many ways, 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, little consistency was observed between studies. Hence, we set out to define a conserved microglia signature of the human central nervous system (CNS), through a comprehensive meta-analysis of existing transcriptomic resources. Nine datasets derived from cells and tissue, isolated from different 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. Comparison of individual microglia clusters showed 249 genes highly conserved between them. This core gene signature included all known markers and improves upon published microglial signatures. The utility of this signature was demonstrated by its use in detecting qualitative and quantitative region-specific alterations in aging and Alzheimers 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 in the contribution of human microglia towards the CNS in health and disease.\n\nTable of ContentsMain points O_LIPublished microglial transcriptional signatures in mouse and human show poor consensus.\nC_LIO_LIA core transcriptional signature of human microglia with 249 genes was derived and found conserved across brain regions, encompassing the CNS.\nC_LIO_LIThe signature revealed region-dependent microglial alterations in Alzheimers, highlighting susceptible CNS regions and the involvement of TYROBP signaling.\nC_LI

neuroscience↗

bioRxiv2017

A High Resolution Atlas Of Gene Expression In The Domestic Sheep (Ovis aries)

Sheep are a key source of meat, milk and fibre for the global livestock sector, and an important biomedical model. Global analysis of gene expression across multiple tissues has aided genome annotation and supported functional annotation of mammalian genes. We present a large-scale RNA-Seq dataset representing all the major organ systems from adult sheep and from several juvenile, neonatal and prenatal developmental time points. The Ovis aries reference genome (Oar v3.1) includes 27,504 genes (20,921 protein coding), of which 25,350 (19,921 protein coding) had detectable expression in at least one tissue in the sheep gene expression atlas dataset. Network-based cluster analysis of this dataset grouped genes according to their expression pattern. The principle of guilt by association was used to infer the function of uncharacterised genes from their co-expression with genes of known function. We describe the overall transcriptional signatures present in the sheep gene expression atlas and assign those signatures, where possible, to specific cell populations or pathways. The findings are related to innate immunity by focusing on clusters with an immune signature, and to the advantages of cross-breeding by examining the patterns of genes exhibiting the greatest expression differences between purebred and crossbred animals. This high-resolution gene expression atlas for sheep is, to our knowledge, the largest transcriptomic dataset from any livestock species to date. It provides a resource to improve the annotation of the current reference genome for sheep, presenting a model transcriptome for ruminants and insight into gene, cell and tissue function at multiple developmental stages.\n\nAuthor SummarySheep are ruminant mammals kept as livestock for the production of meat, milk and wool in agricultural industries across the globe. Genetic and genomic information can be used to improve production traits such as disease resiliance. The sheep genome is however missing important information relating to gene function and many genes, which may be important for productivity, have no informative gene name. This can be remedied using RNA-Sequencing to generate a global expression profile of all protein-coding genes, across multiple organ systems and developmental stages. Clustering genes based on their expression profile across tissues and cells allows us to assign function to those genes. If for example a gene with no informative gene name is expressed in macrophages and is found within a cluster of known macrophage related genes it is likely to be involved in macrophage function and play a role in innate immunity. This information improves the quality of the reference genome and provides insight into biological processes underlying the complex traits that influence the productivity of sheep and other livestock species.

genomics↗

bioRxiv2016

Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease.

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share patterns of transcriptional regulation. Accordingly, shared transcriptional regulation (coexpression) may help prioritise loci associated with a given trait, and help to identify the biological processes underlying it. Using cap analysis of gene expression (CAGE) profiles of promoter and enhancer-derived RNAs across 1824 human samples, we have quantified coexpression of RNAs originating from trait-associated regulatory regions using a novel analytical method (network density analysis; NDA). For most traits studied, sequence variants in regulatory regions were linked to tightly coexpressed networks that are likely to share important functional characteristics. These networks implicate particular cell types and tissues in disease pathogenesis; for example, variants associated with ulcerative colitis are linked to expression in gut tissue, whereas Crohns disease variants are restricted to immune cells. We show that this coexpression signal provides additional independent information for fine mapping likely causative variants. This approach identifies additional genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. This approach enables a deeper biological understanding of the causal basis of complex traits.\n\nONE SENTENCE SUMMARYWe discover that variants associated with a specific disease share expression profiles across tissues and cell types, enabling fine mapping and identification of new disease-associated variants, illuminating key cell types involved in disease pathogenesis.

genomics↗