Enhancers control the correct temporal and cell type-specific activation of gene expression in higher eukaryotes. Knowing their properties, regulatory activity and targets is crucial to understand the regulation of differentiation and homeostasis. We use the FANTOM5 panel of samples covering the majority of human tissues and cell types to produce an atlas of active, in vivo transcribed enhancers. We show that enhancers share properties with CpG-poor mRNA promoters but produce bidirectional, exosome-sensitive, relatively short unspliced RNAs, the generation of which is strongly related to enhancer activity. The atlas is used to compare regulatory programs between different cells at unprecedented depth, identify disease-associated regulatory single nucleotide polymorphisms, and classify cell type-specific and ubiquitous enhancers. We further explore the utility of enhancer redundancy, which explains gene expression strength rather than expression patterns. The online FANTOM5 enhancer atlas represents a unique resource for studies on cell type-specific enhancers and gene regulation.
Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly ‘housekeeping’, whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.
An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumour DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive 'liquid biopsy' for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation marker panel by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumour DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1,098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P < 0.001) and was highly correlated with tumour burden, treatment response, and stage. Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P < 0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC.
The recent advancement of water stable metal-organic frameworks (MOFs) expands the application of this unique porous material. This review article aims at studying their applications in terms of five major areas: adsorption, membrane separation, sensing, catalysis, and proton conduction. These applications are either conducted in a water-containing environment or directly targeted on water treatment processes. The representative and significant studies in each area were comprehensively reviewed and discussed for perspectives, to serve as a reference for researchers working in related areas. At the end, a summary and future outlook on the applications of water stable MOFs are suggested as concluding remarks.
In this study, continuous zirconium(IV)-based metal-organic framework (Zr-MOF) membranes were prepared. The pure-phase Zr-MOF (i.e., UiO-66) polycrystalline membranes were fabricated on alumina hollow fibers using an in situ solvothermal synthesis method. Single-gas permeation and ion rejection tests were carried out to confirm membrane integrity and functionality. The membrane exhibited excellent multivalent ion rejection (e.g., 86.3% for Ca(2+), 98.0% for Mg(2+), and 99.3% for Al(3+)) on the basis of size exclusion with moderate permeance (0.14 L m(-2) h(-1) bar(-1)) and good permeability (0.28 L m(-2) h(-1) bar(-1) μm). Benefiting from the exceptional chemical stability of the UiO-66 material, no degradation of membrane performance was observed for various tests up to 170 h toward a wide range of saline solutions. The high separation performance combined with its outstanding water stability suggests the developed UiO-66 membrane as a promising candidate for water desalination.
Cytochrome c released from mitochondria has been proposed to be an essential component of an apoptotic pathway responsive to DNA damage and other forms of cell stress. Murine embryos devoid of cytochrome c die in utero by midgestation, but cell lines established from early cytochrome c null embryos are viable under conditions that compensate for defective oxidative phosphorylation. As compared to cell lines established from wild-type embryos, cells lacking cytochrome c show reduced caspase-3 activation and are resistant to the proapoptotic effects of UV irradiation, serum withdrawal, or staurosporine. In contrast, cells lacking cytochrome c demonstrate increased sensitivity to cell death signals triggered by TNFalpha. These results define the role of cytochrome c in different apoptotic signaling cascades.
Automated visual-tracking of cell populations in vitro using time-lapse phase contrast microscopy enables quantitative, systematic, and high-throughput measurements of cell behaviors. These measurements include the spatiotemporal quantification of cell migration, mitosis, apoptosis, and the reconstruction of cell lineages. The combination of low signal-to-noise ratio of phase contrast microscopy images, high and varying densities of the cell cultures, topological complexities of cell shapes, and wide range of cell behaviors poses many challenges to existing tracking techniques. This paper presents a fully automated multi-target tracking system that can efficiently cope with these challenges while simultaneously tracking and analyzing thousands of cells observed using time-lapse phase contrast microscopy. The system combines bottom-up and top-down image analysis by integrating multiple collaborative modules, which exploit a fast geometric active contour tracker in conjunction with adaptive interacting multiple models (IMM) motion filtering and spatiotemporal trajectory optimization. The system, which was tested using a variety of cell populations, achieved tracking accuracy in the range of 86.9-92.5%.
scite is a Brooklyn-based startup that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.