The high-dimensional data created by high-throughput technologies require visualization tools that reveal data structure and patterns in an intuitive form. We present PHATE, a visualization method that captures both local and global nonlinear structure using an information-geometric distance between datapoints. We compared PHATE to other tools on a variety of artificial and biological *

Epigenome profiling has led to the paradigm that promoters of active genes are decorated with H3K4me3 and H3K9ac marks. To explore the epigenome of Plasmodium falciparum asexual stages, we performed MS analysis of histone modifications and found a general preponderance of H3/H4 acetylation and H3K4me3. ChIPon-chip profiling of H3, H3K4me3, H3K9me3, and H3K9ac from asynchronous parasites revealed an extensively euchromatic epigenome with heterochromatin restricted to variant surface antigen gene families (VSA) and a number of genes hitherto unlinked to VSA. Remarkably, the vast majority of the genome shows an unexpected pattern of enrichment of H3K4me3 and H3K9ac. Analysis of synchronized parasites revealed significant developmental stage specificity of the epigenome. In rings, H3K4me3 and H3K9ac are homogenous across the genes marking active and inactive genes equally, whereas in schizonts, they are enriched at the 5 end of active genes. This study reveals an unforeseen and unique plasticity in the use of the epigenetic marks and implies the presence of distinct epigenetic pathways in gene silencing/activation throughout the erythrocytic cycle.chromatin ͉ epigenetics ͉ malaria P lasmodium falciparum, the protozoan parasite causing malaria, exhibits a complex life cycle characterized by invasion of different cell types and hosts. During the Ϸ48 h of the intraerythrocytic cycle, a merozoite invades a red blood cell (RBC) and develops into the ring stage, which is followed by the trophozoite stage. Nuclear division marks the beginning of the schizont stage, which results in the formation of up to 32 merozoites that can invade new RBCs (1). Global analysis of transcription (2, 3) and protein expression (4, 5) of the parasite have revealed a high level of coordination in gene expression during the different stages of the life cycle. The absence of chromosomal clustering among genes with similar transitory expression profiles indicates that genes are regulated individually.

Terminal oligopyrimidine (TOP) motifs are sequences at the 5′ ends of mRNAs that link their translation to the mTOR Complex 1 (mTORC1) nutrient-sensing signaling pathway. They are commonly regarded as discrete elements that reside on ∼100 mRNAs that mostly encode translation factors. However, the full spectrum of TOP sequences and their prevalence throughout the transcriptome remain unclear, primarily because of uncertainty over the mechanism that detects them. Here, we globally analyzed translation targets of La-related protein 1 (LARP1), an RNA-binding protein and mTORC1 effector that has been shown to repress TOP mRNA translation in a few specific cases. We establish that LARP1 is the primary translation regulator of mRNAs with classical TOP motifs genome-wide, and also that these motifs are extreme instances of a broader continuum of regulatory sequences. We identify the features of TOP sequences that determine their potency and quantify these as a metric that accurately predicts mTORC1/LARP1 regulation called a TOPscore. Analysis of TOPscores across the transcriptomes of 16 mammalian tissues defines a constitutive “core” set of TOP mRNAs, but also identifies tissue-specific TOP mRNAs produced via alternative transcription initiation sites. These results establish the central role of LARP1 in TOP mRNA regulation on a transcriptome scale and show how it connects mTORC1 to a tunable and dynamic program of gene expression that is tailored to specific biological contexts.

In the era of 'Big Data' there is a pressing need for tools that provide human interpretable visualizations of emergent patterns in high-throughput high-dimensional data. Further, to enable insightful data exploration, such visualizations should faithfully capture and emphasize emergent structures and patterns without enforcing prior assumptions on the shape or form of the data. In this paper, we present PHATE (Potential of Heat-diffusion for Affinity-based Transition Embedding) -an unsupervised low-dimensional embedding for visualization of data that is aimed at solving these issues. Unlike previous methods that are commonly used for visualization, such as PCA and tSNE, PHATE is able to capture and highlight both local and global structure in the data. In particular, in addition to clustering patterns, PHATE also uncovers and emphasizes progression and transitions (when they exist) in the data, which are often missed in other visualization-capable methods. Such 24, 2017; patterns are especially important in biological data that contain, for example, single-cell phenotypes at different phases of differentiation, patients at different stages of disease progression, and gut microbial compositions that vary gradually between individuals, even of the same enterotype.International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/120378 doi: bioRxiv preprint first posted online Mar.The embedding provided by PHATE is based on a novel informational distance that captures long-range nonlinear relations in the data by computing energy potentials of dataadaptive diffusion processes. We demonstrate the effectiveness of the produced visualization in revealing insights on a wide variety of biomedical data, including single-cell RNA-sequencing, mass cytometry, gut microbiome sequencing, human SNP data, Hi-C data, as well as non-biomedical data, such as facebook network and facial image data. In order to validate the capability of PHATE to enable exploratory analysis, we generate a new dataset of 31,000 single-cells from a human embryoid body differentiation system. Here, PHATE provides a comprehensive picture of the differentiation process, while visualizing major and minor branching trajectories in the data. We validate that all known cell types are recapitulated in the PHATE embedding in proper organization. Furthermore, the global picture of the system offered by PHATE allows us to connect parts of the developmental progression and characterize novel regulators associated with developmental lineages.