Deep learning architectures such as variational autoencoders have revolutionized the analysis of transcriptomics data. However, the latent space of these variational autoencoders offers little to no ...interpretability. To provide further biological insights, we introduce a novel sparse Variational Autoencoder architecture, VEGA (VAE Enhanced by Gene Annotations), whose decoder wiring mirrors user-provided gene modules, providing direct interpretability to the latent variables. We demonstrate the performance of VEGA in diverse biological contexts using pathways, gene regulatory networks and cell type identities as the gene modules that define its latent space. VEGA successfully recapitulates the mechanism of cellular-specific response to treatments, the status of master regulators as well as jointly revealing the cell type and cellular state identity in developing cells. We envision the approach could serve as an explanatory biological model for development and drug treatment experiments.
The characteristic ionic currents of nucleotide kmers are commonly used in analyzing nanopore sequencing readouts. We present a graph convolutional network-based deep learning framework for ...predicting kmer characteristic ionic currents from corresponding chemical structures. We show such a framework can generalize the chemical information of the 5-methyl group from thymine to cytosine by correctly predicting 5-methylcytosine-containing DNA 6mers, thus shedding light on the de novo detection of nucleotide modifications.
Type 2 diabetes (T2D) is associated with β-cell dedifferentiation. Aldehyde dehydrogenase 1 isoform A3 (ALHD1A3) is a marker of β-cell dedifferentiation and correlates with T2D progression. However, ...it is unknown whether ALDH1A3 activity contributes to β-cell failure, and whether the decrease of ALDH1A3-positive β-cells (A+) following pair-feeding of diabetic animals is due to β-cell restoration. To tackle these questions, we (i) investigated the fate of A+ cells during pair-feeding by lineage-tracing, (ii) somatically ablated ALDH1A3 in diabetic β-cells, and (iii) used a novel selective ALDH1A3 inhibitor to treat diabetes. Lineage tracing and functional characterization show that A+ cells can be reconverted to functional, mature β-cells. Genetic or pharmacological inhibition of ALDH1A3 in diabetic mice lowers glycemia and increases insulin secretion. Characterization of β-cells following ALDH1A3 inhibition shows reactivation of differentiation as well as regeneration pathways. We conclude that ALDH1A3 inhibition offers a therapeutic strategy against β-cell dysfunction in diabetes.
The maintenance and transition of cellular states are controlled by biological processes. Here we present a gene set-based transformation of single cell RNA-Seq data into biological process ...activities that provides a robust description of cellular states. Moreover, as these activities represent species-independent descriptors, they facilitate the alignment of single cell states across different organisms.
Abstract
Motivation
In a scenario where populations A, B1 and B2 (subpopulations of B) exist, pronounced differences between A and B may mask subtle differences between B1 and B2.
Results
Here we ...present iterClust, an iterative clustering framework, which can separate more pronounced differences (e.g. A and B) in starting iterations, followed by relatively subtle differences (e.g. B1 and B2), providing a comprehensive clustering trajectory.
Availability and implementation
iterClust is implemented as a Bioconductor R package.
Supplementary information
Supplementary data are available at Bioinformatics online.
Chrysanthemum (Chrysanthemum moriforlium Ramat.) is one of the most popular flowers worldwide, with very high ornamental and economic values. However, the limitations of available DNA molecular ...markers and the lack of full genomic sequences hinder the study of genetic diversity and the molecular breeding of chrysanthemum. Here, we developed simple sequence repeat (SSR) from the full-length transcriptome sequences of chrysanthemum cultivar 'Hechengxinghuo'. A total of 11,699 SSRs with mono-, di-, tri-, tetra-, penta- and hexanucleotide repeats were identified, of which eight out of eighteen SSR loci identified based on sixteen transcripts participated in carotenoid metabolism or anthocyanin synthesis were validated as polymorphic SSR markers. These SSRs were used to classify 117 chrysanthemum accessions with different flower colors at the DNA and cDNA levels. The results showed that four SSR markers of carotenoid metabolic pathway divided 117 chrysanthemum accessions into five groups at cDNA level and all purple chrysanthemum accessions were in the group III. Furthermore, the SSR marker CHS-3, LCYE-1 and 3MaT may be related to green color and the PSY-1b marker may be related to yellow color. Overall, our work may be provide a novel method for mining SSR markers associated with specific traits.
Basal cells are multipotent stem cells of a variety of organs, including the respiratory tract, where they are major components of the airway epithelium. However, it remains unclear how diverse basal ...cells are and how distinct subpopulations respond to airway challenges. Using single cell RNA-sequencing and functional approaches, we report a significant and previously underappreciated degree of heterogeneity in the basal cell pool, leading to identification of six subpopulations in the adult murine trachea. Among these, we found two major subpopulations, collectively comprising the most uncommitted of all the pools, but with distinct gene expression signatures. Notably, these occupy distinct ventral and dorsal tracheal niches and differ in their ability to self-renew and initiate a program of differentiation in response to environmental perturbations in primary cultures and in mouse injury models in vivo. We found that such heterogeneity is acquired prenatally, when the basal cell pool and local niches are still being established, and depends on the integrity of these niches, as supported by the altered basal cell phenotype of tracheal cartilage-deficient mouse mutants. Finally, we show that features that distinguish these progenitor subpopulations in murine airways are conserved in humans. Together, the data provide novel insights into the origin and impact of basal cell heterogeneity on the establishment of regionally distinct responses of the airway epithelium during injury-repair and in disease conditions.
We and others have shown that transition and maintenance of biological states is controlled by master regulator proteins, which can be inferred by interrogating tissue-specific regulatory models ...(interactomes) with transcriptional signatures, using the VIPER algorithm. Yet, some tissues may lack molecular profiles necessary for interactome inference (orphan tissues), or, as for single cells isolated from heterogeneous samples, their tissue context may be undetermined. To address this problem, we introduce metaVIPER, an algorithm designed to assess protein activity in tissue-independent fashion by integrative analysis of multiple, non-tissue-matched interactomes. This assumes that transcriptional targets of each protein will be recapitulated by one or more available interactomes. We confirm the algorithm's value in assessing protein dysregulation induced by somatic mutations, as well as in assessing protein activity in orphan tissues and, most critically, in single cells, thus allowing transformation of noisy and potentially biased RNA-Seq signatures into reproducible protein-activity signatures.
We present the Manatee variational autoencoder model to predict transcription factor (TF) perturbation-induced transcriptomes. We demonstrate that the Manatee in silico perturbation analysis ...recapitulates target transcriptomic phenotypes in diverse cellular lineage transitions. We further propose the Manatee in silico screening analysis for prioritizing TF combinations targeting desired transcriptomic phenotypes.
Notch signaling, re-activated in β cells from obese mice and causal to β cell dysfunction, is determined in part by transmembrane ligand availability in a neighboring cell. We hypothesized that β ...cell expression of Jagged1 determines the maladaptive Notch response and resultant insulin secretory defects in obese mice.
We assessed expression of Notch pathway components in high-fat diet-fed (HFD) or leptin receptor-deficient (db/db) mice, and performed single-cell RNA sequencing (scRNA-Seq) in islets from patients with and without type 2 diabetes (T2D). We generated and performed glucose tolerance testing in inducible, β cell-specific Jagged1 gain-of- and loss-of-function mice. We also tested effects of monoclonal neutralizing antibodies to Jagged1 in glucose-stimulated insulin secretion (GSIS) assays in isolated islets.
Jag1 was the only Notch ligand that tracked with increased Notch activity in HFD-fed and db/db mice, as well as in metabolically-inflexible β cells enriched in patients with T2D. Neutralizing antibodies to block Jagged1 in islets isolated from HFD-fed and db/db mice potentiated GSIS ex vivo. To demonstrate if β cell Jagged1 is sufficient to cause glucose tolerance in vivo, we generated inducible β cell-specific Jag1 transgenic (β-Jag1TG) and loss-of-function (iβ-Jag1KO) mice. While forced Jagged1 impaired glucose intolerance due to reduced GSIS, loss of β cell Jagged1 did not protect against HFD-induced insulin secretory defects.
Jagged1 is increased in islets from obese mice and in patients with T2D, and neutralizing Jagged1 antibodies lead to improved GSIS, suggesting that inhibition of Jagged1-Notch signaling may have therapeutic benefit. However, genetic loss-of-function experiments suggest that β cells are not a likely source of the Jagged1 signal.
•Jag1 tracks with increased islet Notch activity in obese mice, and in metabolically inflexible β cells in patients with T2D.•Forced β cell Jagged1 is sufficient to induce glucose intolerance and impair glucose stimulated insulin secretion in mice.•Jagged1 neutralizing antibodies improve glucose stimulatd insulin secretion in islets from obese mice.•Genetic inhibition of β cell Jagged1 does not ameliorate HFD-induced glucose intolerance.
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