High order expression dependencies finely resolve cryptic states and subtypes in single cell data.

Single cells are typically typed by clustering into discrete locations in reduced dimensional transcriptome space. Here we introduce Stator, a data-driven method that identifies cell (sub)types and states without relying on cells' local proximity in transcriptome space. Stator labels the same single cell multiply, not just by type and subtype, but also by state such as activation, maturity or cell cycle sub-phase, through deriving higher-order gene expression dependencies from a sparse gene-by-cell expression matrix.

A TGFβ-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease.

The formation of multiple cysts in the liver occurs in a number of isolated monogenic diseases or multisystemic syndromes, during which bile ducts develop into fluid-filled biliary cysts. For patients with polycystic liver disease (PCLD), nonsurgical treatments are limited, and managing life-long abdominal swelling, pain, and increasing risk of cyst rupture and infection is common. We demonstrate here that loss of the primary cilium on postnatal biliary epithelial cells (via the deletion of the cilia gene ) drives ongoing pathological remodeling of the biliary tree, resulting in progressive cyst formation and growth.

Comparative transcriptome in large-scale human and cattle populations.

Background: Cross-species comparison of transcriptomes is important for elucidating evolutionary molecular mechanisms underpinning phenotypic variation between and within species, yet to date it has been essentially limited to model organisms with relatively small sample sizes.

Results: Here, we systematically analyze and compare 10,830 and 4866 publicly available RNA-seq samples in humans and cattle, respectively, representing 20 common tissues. Focusing on 17,315 orthologous genes, we demonstrate that mean/median gene expression, inter-individual variation of expression, expression quantitative trait loci, and gene co-expression networks are generally conserved between humans and cattle.

Higher-order interactions in statistical physics and machine learning: A model-independent solution to the inverse problem at equilibrium.

The problem of inferring pairwise and higher-order interactions in complex systems involving large numbers of interacting variables, from observational data, is fundamental to many fields. Known to the statistical physics community as the inverse problem, it has become accessible in recent years due to real and simulated big data being generated. Current approaches to the inverse problem rely on parametric assumptions, physical approximations, e.

Pervasive lesion segregation shapes cancer genome evolution.

Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion. Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations.

Zebrafish MITF-Low Melanoma Subtype Models Reveal Transcriptional Subclusters and MITF-Independent Residual Disease.

The melanocyte-inducing transcription factor (MITF)-low melanoma transcriptional signature is predictive of poor outcomes for patients, but little is known about its biological significance, and animal models are lacking. Here, we used zebrafish genetic models with low activity of Mitfa (MITF-low) and established that the MITF-low state is causal of melanoma progression and a predictor of melanoma biological subtype. MITF-low zebrafish melanomas resembled human MITF-low melanomas and were enriched for stem and invasive (mesenchymal) gene signatures.