Biology subjects

Quake, S.

Publications and source records attributed to Quake, S..

5 recordsLinked to original sources

bioRxiv2018

A mouse tissue atlas of small non-coding RNA

Small non-coding RNAs (ncRNAs) play a vital role in a broad range of biological processes both in health and disease. A comprehensive quantitative reference of small ncRNA expression would significantly advance our understanding of ncRNA roles in shaping tissue functions. Here, we systematically profiled the levels of five ncRNA classes (miRNA, snoRNA, snRNA, scaRNA and tRNA fragments) across eleven mouse tissues by deep sequencing. Using fourteen biological replicates spanning both sexes, we identified that ~ 30% of small ncRNAs are distributed across the body in a tissue-specific manner with some are also being sexually dimorphic. We found that miRNAs are subject to "arm switching" between healthy tissues and that tRNA fragments are retained within tissues in both a gene- and a tissue-specific manner. Out of eleven profiled tissues we confirmed that brain contains the largest number of unique small ncRNA transcripts, some of which were previously annotated while others are identified for the first time in this study. Furthermore, by combining these findings with single-cell ATAC-seq data, we were able to connect identified brain-specific ncRNA with their cell types of origin. These results yield the most comprehensive characterization of specific and ubiquitous small RNAs in individual murine tissues to date, and we expect that this data will be a resource for the further identification of ncRNAs involved in tissue-function in health and dysfunction in disease. HIGHLIGHTS- An atlas of tissue levels of multiple small ncRNA classes generated from 14 biological replicates of both sexes across 11 tissues - Distinct distribution patterns of miRNA arms and tRNA fragments across tissues suggest the existence of tissue-specific mechanisms of ncRNA cleavage and retention - miRNA expression is sex specific in healthy tissues - Small RNA-seq and scATAC-seq data integration produce a detailed map of cell-type specific ncRNA profiles in the mouse brain

genomics↗

bioRxiv2018

Hydrogenotrophic methanogenesis in archaeal phylum Verstraetearchaeota reveals the shared ancestry of all methanogens

Methanogenic archaea are major contributors to the global carbon cycle and were long thought to belong exclusively to the euryarchaeotal phylum. Discovery of the methanogenesis gene cluster methyl-coenzyme M reductase (Mcr) in the Bathyarchaeota and thereafter the Verstraetearchaeota led to a paradigm shift, pushing back the evolutionary origin of methanogenesis to pre-date that of the Euryarchaeota. The methylotrophic methanogenesis found in the non-Euryarchaota distinguished itself from the predominantly hydrogenotrophic methanogens found in euryarchaeal orders as the former do not couple methanogenesis to carbon fixation through the reductive acetyl-coenzyme A (Wood-Ljungdahl) pathway, which was interpreted as evidence for independent evolution of the two methanogenesis pathways. Here, we report the discovery of a complete and divergent hydrogenotrophic methanogenesis pathway in a novel, thermophilic order of the Verstraetearchaeota which we have named Candidatus Methanohydrogenales, as well as the presence of the Wood-Ljungdahl pathway in the crenarchaeal order Desulfurococcales. Our findings support the ancient origin of hydrogenotrophic methanogenesis, suggest that methylotrophic methanogenesis might be a later adaptation of specific orders, and provide insight into how transition from hydrogenotrophic to methylotrophic methanogenesis might occur.

microbiology↗

bioRxiv2018

Virus-inclusive single cell RNA sequencing reveals molecular signature predictive of progression to severe dengue infection

Dengue virus (DENV) infection can result in severe complications. Yet, the understanding of the molecular correlates of severity is limited, partly due to difficulties in defining the peripheral blood mononuclear cells (PBMCs) that are associated with DENV in vivo. Additionally, there are currently no biomarkers predictive of progression to severe dengue (SD). Bulk transcriptomics data are difficult to interpret because blood consists of multiple cell types that may react differently to infection. Here we applied virus-inclusive single cell RNA-seq approach (viscRNA-Seq) to profile transcriptomes of thousands of single PBMCs derived early in the course of disease from six dengue patients and four healthy controls, and to characterize distinct DENV-associated leukocytes. Multiple genes, particularly interferon response genes, were upregulated in a cell-specific manner prior to progression to SD. Expression of MX2 in naive B cells and CD163 in CD14+ CD16+ monocytes was predictive of SD. The majority of DENV-associated cells in the blood of two patients who progressed to SD were naive IgM B cells expressing the CD69 and CXCR4 receptors and antiviral genes, followed by monocytes. Bystander uninfected B cells also demonstrated immune activation, and plasmablasts from two patients exhibited antibody lineages with convergently hypermutated heavy chain sequences. Lastly, assembly of the DENV genome revealed diversity at unexpected genomic sites. This study presents a multi-faceted molecular elucidation of natural dengue infection in humans and proposes biomarkers for prediction of SD, with implications for profiling any tissue and viral infection, and for the development of a dengue prognostic assay.\n\nSignificanceA fraction of the 400 million people infected with dengue annually progresses to severe dengue (SD). Yet, there are currently no biomarkers to effectively predict disease progression. We profiled the landscape of host transcripts and viral RNA in thousands of single blood cells from dengue patients prior to progressing to SD. We discovered cell-type specific immune activation and candidate predictive biomarkers. We also revealed preferential virus association with specific cell populations, particularly naive B cells and monocytes. We then explored immune activation of bystander cells, clonality and somatic evolution of adaptive immune repertoires, and viral genomics. This multi-faceted approach could advance understanding of pathogenesis of any viral infection, map an atlas of infected cells and promote the development of prognostics.

immunology↗

bioRxiv2018

Aged blood inhibits hippocampal neurogenesis and activates microglia through VCAM1 at the blood-brain barrier

An aged circulatory environment can promote brain dysfunction and we hypothesized that the blood-brain barrier (BBB) mediates at least some of these effects. We observe brain endothelial cells (BECs) in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of Vascular Cell Adhesion Molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, the shed, soluble form of VCAM1 is prominently increased in the aged circulation of humans and mice, and aged plasma is sufficient to increase VCAM1 expression in cultured BECs and young mouse hippocampi. Systemic anti-VCAM1 antibody or genetic ablation of VCAM1 in BECs counteracts the detrimental effects of aged plasma on young brains and reverses aging aspects in old mouse brains. Thus, VCAM1 is a negative regulator of adult neurogenesis and inducer of microglial reactivity, establishing VCAM1 and the luminal side of the BBB as possible targets to treat age-related neurodegeneration.

neuroscience↗

bioRxiv2017

PhaMers identifies novel bacteriophage sequences from thermophilic hot springs

Metagenomic sequencing approaches have become popular for the purpose of dissecting environmental microbial diversity, leading to the characterization of novel microbial lineages. In addition of bacterial and fungal genomes, metagenomic analysis can also reveal genomes of viruses that infect microbial cells. Because of their small genome size and limited knowledge of phage diversity, discovering novel phage sequences from metagenomic data is often challenging. Here we describe PhaMers (Phage k-Mers). a phage identification tool that uses supervised learning to classify metagenomic contigs as phage or non-phage on the basis of tetranucleotide frequencies. a technique that does not depend on existing gene annotations. PhaMers compares the tetranucleotide frequencies of metagenomic contigs to phage and bacteria references from online databases. resulting in assignments of lower level phage taxonomy based on sequence similarity. Using PhaMers. we identified 103 novel phage sequences from hot spring samples of Yellowstone National Park based on data generated from a microfluidic-based minimetagenomic approach. We analyzed assembled contigs over 5 kbp in length using PhaMers and compared the results with those generated by VirSorter, a publicly available phage identification and annotation package. We analyzed the performance of phage genome prediction and taxonomic classification using PhaMers. and presented putative hosts and taxa for some of the novel phage sequences. Finally. mini-metagenomic occurrence profiles of phage and prokaryotic genomes were used to verify putative hosts.

bioinformatics↗