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Nature Studies Present Tool for Imaging Accessible Genome, Another Tool for Mapping Cells to Clone of Origin, More

A new tool for super-resolution imaging of the accessible genome is described in Nature Methods this week. Dubbed ATAC-PALM, it is a three-dimensional assay for transposase-accessible chromatin-photoactivated localization microscopy that integrates an assay for transposase-accessible chromatin with visualization, PALM super-resolution imaging, and lattice light-sheet microscopy. According to its developers from the Howard Hughes Medical Institute's Janelia Research Campus and elsewhere, 3D ATAC-PALM can be multiplexed with oligopaint DNA-fluorescence in situ hybridization (FISH), RNA-FISH, and protein fluorescence to reveal spatially segregated accessible chromatin domains that enclose active chromatin and transcribed genes.

A team led by scientists from the European Molecular Biology Laboratory have developed a computational tool that uses variant information in scRNA-seq reads to map cells to their clone of origin. The software, called Cardelino, "flexibly integrates information from imperfect clonal trees inferred based on bulk exome-seq data, and sparse variant alleles expressed in scRNA-seq data," its developers write in Nature Methods this week. The researchers apply Cardelino to a published cancer dataset and to newly generated matched scRNAseq and exome-seq data from 32 human dermal fibroblast lines, identifying hundreds of differentially expressed genes between cells from different somatic clones. Cardelino, they write, can be scaled to multisite samples and thousands of cells, making it applicable to high-resolution studies of clonal gene expression in both healthy and malignant cell populations, as well as in vitro models. It may also be effective for other single-cell omics assays that capture somatic variant information, such as those profiling chromatin accessibility or methylation.

A CRISPR-based screening system that enables the comprehensive mapping of genetic interactions (GIs) and functional interrogation of sizable genomic fragments in mammalian cells is reported by a University of Toronto group in Nature Biotechnology this week. The system — called Cas Hybrid for Multiplexed Editing and screening Applications, or CHyMErA — combines the co-expression of Cas9 and Cas12a and machine learning-optimized libraries of hybrid Cas9-Cas12a guide RNAs. According to the researchers, applying CHyMErA to the ablation of mammalian paralog gene pairs reveals extensive GIs and uncovers phenotypes normally masked by functional redundancy, while its use in a chemogenetic interaction screen identifies genes that impact cell growth in response to mTOR pathway inhibition. "Moreover, by systematically targeting thousands of alternative splicing events, CHyMErA identifies exons underlying human cell line fitness. CHyMErA thus represents an effective screening approach for GI mapping and the functional analysis of sizable genomic regions, such as alternative exons," they write. GenomeWeb has more on this here.