C99, not beta-amyloid, is associated with selective death of vulnerable neurons in Alzheimer's disease. Supplementary, bioRxiv, 2019-01-23
Amyloid Precursor Protein (APP) and its cleavage product beta-amyloid are widely believed to be key players in the development of Alzheimer's disease (AD). However, the distribution of amyloid deposits in the brain does not correlate well with disease progression. Therefore, it seemed possible that APP metabolites other than beta-amyloid might make a strong contribution to AD pathology. We developed a sensitive assay adapted to the detection of C99, an intermediate in the conversion of APP to beta-amyloid. Brain tissue sections were obtained from patients suffering from sporadic AD and non-demented controls. Our results demonstrate that C99 levels, but not Abeta levels, correlate with the degree of vulnerability to neurodegeneration and cognitive impairment in patients suffering from AD.
biorxiv neuroscience 100-200-users 2019DNA methylation directs polycomb-dependent 3D genome re- organisation in naive pluripotency Supplementary information, bioRxiv, 2019-01-23
The DNA hypomethylation that occurs when embryonic stem cells (ESCs) are directed to the ground state of naive pluripotency by culturing in 2i conditions results in redistribution of polycomb (H3K27me3) away from its target loci. Here we demonstrate that 3D genome organisation is also altered in 2i. We found chromatin decompaction at polycomb target loci as well as loss of long-range polycomb interactions. By preventing DNA hypomethylation during the transition to the ground-state, we are able to restore the H3K27me3 distribution, and polycomb-mediated 3D genome organisation that is characteristic of primed ESCs grown in serum, to ESCs in 2i. However, these cells retain the functional characteristics of 2i ground state ESCs. Our findings demonstrate the central role of DNA methylation in shaping major aspects of 3D genome organisation but caution against assuming causal roles for the epigenome and 3D genome in gene regulation and function in ESCs.
biorxiv cell-biology 0-100-users 2019Phase separation provides a mechanism to reduce noise in cells Supplementary text, bioRxiv, 2019-01-23
A central problem in cellular control is how cells cope with the inherent noise in gene expression. Although transcriptional and posttranscriptional feedback mechanisms can suppress noise, they are often slow, and cannot explain how cells buffer acute fluctuations. Here, by using a physical model that links fluctuations in protein concentration to the theory of phase separation, we show that liquid droplets can act as fast and effective buffers for gene expression noise. We confirm our theory experimentally using an engineered phase separating protein that forms liquid-like compartments in mammalian cells. These data suggest a novel role of phase separation in biological information processing.
biorxiv biophysics 0-100-users 2019The Malaria Cell Atlas a comprehensive reference of single parasite transcriptomes across the complete Plasmodium life cycle file S1, bioRxiv, 2019-01-23
Malaria parasites adopt a remarkable variety of morphological life stages as they transition through multiple mammalian host and mosquito vector environments. Here we profile the single-cell transcriptomes of thousands of individual parasites, deriving the first high-resolution transcriptional atlas of the entire Plasmodium berghei life cycle. We then use our atlas to precisely define developmental stages of single cells from three different human malaria parasite species, including parasites isolated directly from infected individuals. The Malaria Cell Atlas provides both a comprehensive view of gene usage in a complex eukaryotic parasite and an open access reference data set for the study of malaria parasites.
biorxiv genomics 100-200-users 2019Accurate detection of m6A RNA modifications in native RNA sequences, bioRxiv, 2019-01-21
The field of epitranscriptomics has undergone an enormous expansion in the last few years; however, a major limitation is the lack of generic methods to map RNA modifications transcriptome-wide. Here we show that using Oxford Nanopore Technologies, N6-methyladenosine (m6A) RNA modifications can be detected with high accuracy, in the form of systematic errors and decreased base-calling qualities. Our results open new avenues to investigate the universe of RNA modifications with single nucleotide resolution, in individual RNA molecules.
biorxiv molecular-biology 100-200-users 2019