A compendium of Amplification-Related Gain Of Sensitivity genes in human cancer.

While the effect of amplification-induced oncogene expression in cancer is known, the impact of copy-number gains on "bystander" genes is less understood. We create a comprehensive map of dosage compensation in cancer by integrating expression and copy number profiles from over 8000 tumors in The Cancer Genome Atlas and cell lines from the Cancer Cell Line Encyclopedia. Additionally, we analyze 17 cancer open reading frame screens to identify genes toxic to cancer cells when overexpressed.

ARID1A mutations protect follicular lymphoma from FAS-dependent immune surveillance by reducing RUNX3/ETS1-driven FAS-expression.

The cell death receptor FAS and its ligand (FASLG) play crucial roles in the selection of B cells during the germinal center (GC) reaction. Failure to eliminate potentially harmful B cells via FAS can lead to lymphoproliferation and the development of B cell malignancies. The classic form of follicular lymphoma (FL) is a prototypic GC-derived B cell malignancy, characterized by the t(14;18)(q32;q21)IGH::BCL2 translocation and overexpression of antiapoptotic BCL2.

BioPathNet: Enhancing Link Prediction in Biomedical Knowledge Graphs through Path Representation Learning.

Understanding complex interactions in biomedical networks is crucial for advancements in biomedicine, but traditional link prediction (LP) methods are limited in capturing this complexity. Representation-based learning techniques improve prediction accuracy by mapping nodes to low-dimensional embeddings, yet they often struggle with interpretability and scalability. We present BioPathNet, a novel graph neural network framework based on the Neural Bellman-Ford Network (NBFNet), addressing these limitations through path-based reasoning for LP in biomedical knowledge graphs.

Path-based reasoning for biomedical knowledge graphs with BioPathNet.

Understanding complex interactions in biomedical networks is crucial for advancements in biomedicine, but traditional link prediction (LP) methods are limited in capturing this complexity. Representation-based learning techniques improve prediction accuracy by mapping nodes to low-dimensional embeddings, yet they often struggle with interpretability and scalability. We present BioPathNet, a novel graph neural network framework based on the Neural Bellman-Ford Network (NBFNet), addressing these limitations through path-based reasoning for LP in biomedical knowledge graphs.

Direct neuronal reprogramming of mouse astrocytes is associated with multiscale epigenome remodeling and requires Yy1.

Direct neuronal reprogramming is a promising approach to regenerate neurons from local glial cells. However, mechanisms of epigenome remodeling and co-factors facilitating this process are unclear. In this study, we combined single-cell multiomics with genome-wide profiling of three-dimensional nuclear architecture and DNA methylation in mouse astrocyte-to-neuron reprogramming mediated by Neurogenin2 (Ngn2) and its phosphorylation-resistant form (PmutNgn2), respectively.

Single-cell metabolic profiling reveals subgroups of primary human hepatocytes with heterogeneous responses to drug challenge.

Background: Xenobiotics are primarily metabolized by hepatocytes in the liver, and primary human hepatocytes are the gold standard model for the assessment of drug efficacy, safety, and toxicity in the early phases of drug development. Recent advances in single-cell genomics demonstrate liver zonation and ploidy as main drivers of cellular heterogeneity. However, little is known about the impact of hepatocyte specialization on liver function upon metabolic challenge, including hepatic metabolism, detoxification, and protein synthesis.

CSF3R T618I Collaborates With RUNX1-RUNX1T1 to Expand Hematopoietic Progenitors and Sensitizes to GLI Inhibition.

Activating colony-stimulating factor-3 receptor gene () mutations are recurrent in acute myeloid leukemia (AML) with t(8;21) translocation. However, the nature of oncogenic collaboration between alterations of and the t(8;21) associated fusion remains unclear. In CD34+ hematopoietic stem and progenitor cells from healthy donors, double oncogene expression led to a clonal advantage, increased self-renewal potential, and blast-like morphology and distinct immunophenotype.

epiAneufinder identifies copy number alterations from single-cell ATAC-seq data.

Single-cell open chromatin profiling via scATAC-seq has become a mainstream measurement of open chromatin in single-cells. Here we present epiAneufinder, an algorithm that exploits the read count information from scATAC-seq data to extract genome-wide copy number alterations (CNAs) for individual cells, allowing the study of CNA heterogeneity present in a sample at the single-cell level. Using different cancer scATAC-seq datasets, we show that epiAneufinder can identify intratumor clonal heterogeneity in populations of single cells based on their CNA profiles.

Brief homogeneous TCR signals instruct common iNKT progenitors whose effector diversification is characterized by subsequent cytokine signaling.

Innate-like T cell populations expressing conserved TCRs play critical roles in immunity through diverse developmentally acquired effector functions. Focusing on the prototypical lineage of invariant natural killer T (iNKT) cells, we sought to dissect the mechanisms and timing of fate decisions and functional effector differentiation. Utilizing induced expression of the semi-invariant NKT cell TCR on double positive thymocytes, an initially highly synchronous wave of iNKT cell development was triggered by brief homogeneous TCR signaling.

EpiScanpy: integrated single-cell epigenomic analysis.

EpiScanpy is a toolkit for the analysis of single-cell epigenomic data, namely single-cell DNA methylation and single-cell ATAC-seq data. To address the modality specific challenges from epigenomics data, epiScanpy quantifies the epigenome using multiple feature space constructions and builds a nearest neighbour graph using epigenomic distance between cells. EpiScanpy makes the many existing scRNA-seq workflows from scanpy available to large-scale single-cell data from other -omics modalities, including methods for common clustering, dimension reduction, cell type identification and trajectory learning techniques, as well as an atlas integration tool for scATAC-seq datasets.

Region-level epimutation rates in Arabidopsis thaliana.

Failure to maintain DNA methylation patterns during plant development can occasionally give rise to so-called "spontaneous epimutations". These stochastic methylation changes are sometimes heritable across generations and thus accumulate in plant genomes over time. Recent evidence indicates that spontaneous epimutations have a major role in shaping patterns of methylation diversity in plant populations.

A genome assembly and the somatic genetic and epigenetic mutation rate in a wild long-lived perennial Populus trichocarpa.

Background: Plants can transmit somatic mutations and epimutations to offspring, which in turn can affect fitness. Knowledge of the rate at which these variations arise is necessary to understand how plant development contributes to local adaption in an ecoevolutionary context, particularly in long-lived perennials.

Results: Here, we generate a new high-quality reference genome from the oldest branch of a wild Populus trichocarpa tree with two dominant stems which have been evolving independently for 330 years.

AlphaBeta: computational inference of epimutation rates and spectra from high-throughput DNA methylation data in plants.

Stochastic changes in DNA methylation (i.e., spontaneous epimutations) contribute to methylome diversity in plants.

Author Correction: Widespread long-range cis-regulatory elements in the maize genome.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Altering microtubule dynamics is synergistically toxic with spindle assembly checkpoint inhibition.

Chromosomal instability (CIN) and aneuploidy are hallmarks of cancer. As most cancers are aneuploid, targeting aneuploidy or CIN may be an effective way to target a broad spectrum of cancers. Here, we perform two small molecule compound screens to identify drugs that selectively target cells that are aneuploid or exhibit a CIN phenotype.

Widespread long-range cis-regulatory elements in the maize genome.

Genetic mapping studies on crops suggest that agronomic traits can be controlled by gene-distal intergenic loci. Despite the biological importance and the potential agronomic utility of these loci, they remain virtually uncharacterized in all crop species to date. Here, we provide genetic, epigenomic and functional molecular evidence to support the widespread existence of gene-distal (hereafter, distal) loci that act as long-range transcriptional cis-regulatory elements (CREs) in the maize genome.

Gene networks in cancer are biased by aneuploidies and sample impurities.

Gene regulatory network inference is a standard technique for obtaining structured regulatory information from, for instance, gene expression measurements. Methods performing this task have been extensively evaluated on synthetic, and to a lesser extent real data sets. In contrast to these test evaluations, applications to gene expression data of human cancers are often limited by fewer samples and more potential regulatory links, and are biased by copy number aberrations as well as cell mixtures and sample impurities.

breakpointR: an R/Bioconductor package to localize strand state changes in Strand-seq data.

Motivation: Strand-seq is a specialized single-cell DNA sequencing technique centered around the directionality of single-stranded DNA. Computational tools for Strand-seq analyses must capture the strand-specific information embedded in these data.

Results: Here we introduce breakpointR, an R/Bioconductor package specifically tailored to process and interpret single-cell strand-specific sequencing data obtained from Strand-seq.

Quantification of Aneuploidy in Mammalian Systems.

High-throughput next generation sequencing karyotyping has emerged as a powerful tool for the detection of genomic heterogeneity in normal tissues and cancers. Here we describe a single-cell whole genome sequencing (scWGS) platform to assess whole-chromosome aneuploidy, structural aneuploidies involving only chromosome fragments and more local small copy number alterations in individual cells. We provide a detailed protocol for the isolation, library preparation, low coverage sequencing and data analysis of single cells.

METHimpute: imputation-guided construction of complete methylomes from WGBS data.

Background: Whole-genome bisulfite sequencing (WGBS) has become the standard method for interrogating plant methylomes at base resolution. However, deep WGBS measurements remain cost prohibitive for large, complex genomes and for population-level studies. As a result, most published plant methylomes are sequenced far below saturation, with a large proportion of cytosines having either missing data or insufficient coverage.

Histone propionylation is a mark of active chromatin.

Histones are highly covalently modified, but the functions of many of these modifications remain unknown. In particular, it is unclear how histone marks are coupled to cellular metabolism and how this coupling affects chromatin architecture. We identified histone H3 Lys14 (H3K14) as a site of propionylation and butyrylation in vivo and carried out the first systematic characterization of histone propionylation.

Ecological plant epigenetics: Evidence from model and non-model species, and the way forward.

Growing evidence shows that epigenetic mechanisms contribute to complex traits, with implications across many fields of biology. In plant ecology, recent studies have attempted to merge ecological experiments with epigenetic analyses to elucidate the contribution of epigenetics to plant phenotypes, stress responses, adaptation to habitat, and range distributions. While there has been some progress in revealing the role of epigenetics in ecological processes, studies with non-model species have so far been limited to describing broad patterns based on anonymous markers of DNA methylation.