The GTEx Consortium atlas of genetic regulatory effects across human tissues, bioRxiv, 2019-10-03
AbstractThe Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues, and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing incisandtrans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue-specificity of genetic effects, and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
biorxiv genetics 500+-users 2019Natural image reconstruction from brain waves a novel visual BCI system with native feedback, bioRxiv, 2019-10-02
AbstractHere we hypothesize that observing the visual stimuli of different categories trigger distinct brain states that can be decoded from noninvasive EEG recordings. We introduce an effective closed-loop BCI system that reconstructs the observed or imagined stimuli images from the co-occurring brain wave parameters. The reconstructed images are presented to the subject as a visual feedback. The developed system is applicable to training BCI-naïve subjects because of the user-friendly and intuitive way the visual patterns are employed to modify the brain states.
biorxiv neuroscience 200-500-users 2019Molecular Cross-Validation for Single-Cell RNA-seq, bioRxiv, 2019-10-01
Single-cell RNA sequencing enables researchers to study the gene expression of individual cells. However, in high-throughput methods the portrait of each individual cell is noisy, representing thousands of the hundreds of thousands of mRNA molecules originally present. While many methods for denoising single-cell data have been proposed, a principled procedure for selecting and calibrating the best method for a given dataset has been lacking. We present “molecular cross-validation,” a statistically principled and data-driven approach for estimating the accuracy of any denoising method without the need for ground-truth. We validate this approach for three denoising methods—principal component analysis, network diffusion, and a deep autoencoder—on a dataset of deeply-sequenced neurons. We show that molecular cross-validation correctly selects the optimal parameters for each method and identifies the best method for the dataset.
biorxiv bioinformatics 200-500-users 2019Mammalian Y RNAs are modified at discrete guanosine residues with N-glycans, bioRxiv, 2019-09-30
ABSTRACTGlycans modify lipids and proteins to mediate inter- and intramolecular interactions across all domains of life. RNA, another multifaceted biopolymer, is not thought to be a major target of glycosylation. Here, we challenge this view with evidence that mammalian cells use RNA as a third scaffold for glycosylation in the secretory pathway. Using a battery of chemical and biochemical approaches, we find that a select group of small noncoding RNAs including Y RNAs are modified with complex, sialylated N-glycans (glycoRNAs). These glycoRNA are present in multiple cell types and mammalian species, both in cultured cells andin vivo. Finally, we find that RNA glycosylation depends on the canonical N-glycan biosynthetic machinery within the ERGolgi luminal spaces. Collectively, these findings suggest the existence of a ubiquitous interface of RNA biology and glycobiology suggesting an expanded role for glycosylation beyond canonical lipid and protein scaffolds.
biorxiv molecular-biology 500+-users 2019Architectural RNA is required for heterochromatin organization, bioRxiv, 2019-09-28
AbstractIn addition to its known roles in protein synthesis and enzyme catalysis, RNA has been proposed to stabilize higher-order chromatin structure. To distinguish presumed architectural roles of RNA from other functions, we applied a ribonuclease digestion strategy to our CUT&RUN in situ chromatin profiling method (CUT&RUN.RNase). We find that depletion of RNA compromises association of the murine nucleolar protein Nucleophosmin with pericentric heterochromatin and alters the chromatin environment of CCCTC-binding factor (CTCF) bound regions. Strikingly, we find that RNA maintains the integrity of both constitutive (H3K9me3 marked) and facultative (H3K27me3 marked) heterochromatic regions as compact domains, but only moderately stabilizes euchromatin. To establish the specificity of heterochromatin stabilization by RNA, we performed CUT&RUN on cells deleted for the Firre long non-coding RNA and observed disruption of H3K27me3 domains on several chromosomes. We conclude that RNA maintains local and global chromatin organization by acting as a structural scaffold for heterochromatic domains.
biorxiv genomics 100-200-users 2019FMRP promotes RNA localization to neuronal projections through interactions between its RGG domain and G-quadruplex RNA sequences, bioRxiv, 2019-09-28
ABSTRACTThe sorting of RNA molecules to distinct subcellular locations facilitates the activity of spatially restricted processes through local protein synthesis. This process affects thousands of transcripts yet precisely how these RNAs are trafficked to their destinations remains generally unclear. Here we have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these FMRP RNA localization targets contain a large enrichment of G-quadruplex sequences, particularly in their 3′ UTRs, suggesting that FMRP recognizes these sequences to promote the localization of transcripts that contain them. Fractionation of neurons derived from human Fragile X Syndrome patients revealed a high degree of conservation in the identity of FMRP localization targets between human and mouse as well as an enrichment of G-quadruplex sequences in human FMRP RNA localization targets. Using high-throughput RNAprotein interaction assays and single-molecule RNA FISH, we identified the RGG domain of FMRP as important for both interaction with G-quadruplex RNA sequences and the neuronal transport of G-quadruplex-containing transcripts. Finally, we used ribosome footprinting to identify translational regulatory targets of FMRP. The translational regulatory targets were not enriched for G-quadruplex sequences and were largely distinct from the RNA localization targets of FMRP, indicating that the two functions can be biochemically separated and are mediated through different target recognition mechanisms. These results establish a molecular mechanism underlying FMRP-mediated neuronal RNA localization and provide a framework for the elucidation of similar mechanisms governed by other RNA-binding proteins.
biorxiv molecular-biology 0-100-users 2019